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European Journal of Medicinal Chemistry 142 (2017) 179e212

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European Journal of Medicinal Chemistry


journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Recent advances (2015e2016) in anticancer hybrids


Nagaraju Kerru a, Parvesh Singh a, **, Neil Koorbanally a, Raghu Raj b, Vipan Kumar c, *
a
School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban 4000, South Africa
b
Department of Chemistry, DAV College, Amritsar 143001, India
c
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India

a r t i c l e i n f o a b s t r a c t

Article history: In spite of the development of a large number of novel anticancer drugs over the years, Cancer remains as
Received 31 May 2017 a prominent cause of death, worldwide. Numerous drugs that are currently in clinical practice have
Received in revised form developed multidrug resistance along with fatal side effects. Therefore, the utilization of single-target
13 July 2017
therapy is incapable of providing an effective control on the malignant process. Molecular hybridiza-
Accepted 18 July 2017
Available online 20 July 2017
tion, involving a combination of two or more pharmacophores of bioactive scaffolds to generate a single
molecular architecture with improved affinity and activity, in comparison to their parent molecules, has
emerged as a promising strategy in recent drug discovery research. Hybrid anticancer drugs are of great
Keywords:
Cancer
therapeutic interests since they can potentially overcome most of the pharmacokinetic drawbacks
Anticancer hybrids encountered with conventional anticancer drugs. Strategically, the design of anticancer drugs involved
Structure-activity relationship the blending or linking of an anticancer drug with another anticancer drug or a carrier molecule which
Mechanism of action can efficiently target cancer cells with improved biological potential. Major advantages of hybrid anti-
cancer drugs involved increased specificity, better patient compliance, and lower side effects along with
reduction in chemo-resistance. The successful utilization of this technique in design and synthesis of
novel anticancer hybrids has been well illustrated and documented in the literature. The purpose of the
present review article will be to provide an emphasis on the recent developments (2015e16) in anti-
cancer hybrids with insights into their structure-activity relationship (SAR) and mechanism of action.
© 2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2. Anticancer molecular hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2.1. Curcumin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2.2. Benzimidazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.3. Pyrimidine based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
2.4. Coumarin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
2.5. Pyrazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
2.6. Quinoline based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.7. Quinone based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.8. Quinazoline based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.9. Pyridine based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.10. Triazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
2.11. Isatin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
2.11.1. Chalcone based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
2.12. Imidazole based hybrid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2.13. Selenium/sulfur based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

* Corresponding author.
** Corresponding author.
E-mail addresses: singhp4@ukzn.ac.za (P. Singh), vipan_org@yahoo.com
(V. Kumar).

http://dx.doi.org/10.1016/j.ejmech.2017.07.033
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
180 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

2.14. Nitric oxide (NO) releasing hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206


2.15. Natural product based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.15.1. Drug modified anticancer hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

1. Introduction normal proliferating tissues such as hematopoietic system [10,11].


Consequently, in the development of effectual and discerning
Cancer is a major health encumbrance in both developed and anticancer drugs having low incidence of side effects, toxicity and
underdeveloped countries involving numerous spatiotemporal emergence of drug resistance is of high priority [12]. To address this
changes in cell physiology. According to the World Health Organi- issue, combination therapy was considered, where numerous
zation (WHO) report, 8.8 million people died of cancer globally in cytotoxic hybrids were pooled in anticancer behaviour regimes that
2015 [1]. A recent survey by the American Cancer Society of epi- endorse improved results with fewer side effects. However, the
demiologists revealed that approximately one-third of 595,690 advantage of combination pattern is compromised with poor pa-
cancer deaths in the USA were due to smoking, the main cause of tient compliance [13,14].
lung cancer that accounted for the highest number of cancer deaths The hybrid anticancer drug approach is an innovative synthetic
(Fig. 1) worldwide [2]. In addition, 20% of all cancers diagnosed are strategy that involves either the merging or blending of hepato-
associated with obesity, physical inactivity, excess alcohol con- phoric moieties of different drugs in a new molecular structure or
sumption, and/or poor nutrition while certain cancers are related to combining two or more potential anticancer pharmacophores
infections caused by the human papilloma virus (HPV), hepatitis B directly through cleavable/non-cleavable linkages, based on the
virus (HBV), hepatitis C virus (HCV), human immunodeficiency ability of moieties to retain their affinity and activity for biological
virus (HIV), and Helicobacter pylori (H. pylori). These cancers could targets in the newly synthesized molecular hybrid. It is believed
be circumvented through behavioural changes, vaccination, or by that the presence of two or more pharmacophores in a single unit
treating the infection. not only synergises their biological effect but also upsurge their
Most cancers are recognized by uninhibited growth of cells ability to inhibit more than one biological target. Recently, the
without demarcation due to the deregulation of crucial enzymes molecular hybrid approach has resulted in several novel chemical
and proteins controlling cell division and proliferation [3,4]. The entities with improved anticancer activity and selectivity with
biological process responsible for the transformation of normal reduced side effects. This review covers the period 2015e2016 and
cells into malignant cancer cells has been the focus of research focuses on the diverse strategies for pharmaco-modulation focused
endeavours in the biomedical sciences. Although much progress on innovative hybrid compounds exhibiting promising anticancer
has been aspired from the identification to the treatment of cancer, activities, along with a brief summary of their structure-activity
factors like poor patient compliance, drug resistance and drug relationship (SAR).
induced toxicities has provided a strong impetus for the discovery
and development of novel cancer chemotherapeutic hybrids of
clinical significance [5e7]. Anticancer drugs have been categorized 2. Anticancer molecular hybrids
in consonance with their mechanism of action as molecular tar-
geting hybrids, antimetabolites, antitubulin and DNA-interactive 2.1. Curcumin based hybrids
hybrids, monoclonal antibodies and hormones [8,9]. However, the
single target approach also leads to cytotoxicity, predominantly on Curcumin, a naturally occurring polyphenolic compound is one
of the most extensively researched chemopreventive agents with
high safety profile in humans, as validated by Food and Drug
Administration (FDA) [15]. Mechanistically, curcumin inhibits the
self-assembly of tubulin via binding with it at 32 Å away from
colchicine-binding site, however the precise mechanism of action is
still not certain [16]. However, the clinical efficacy of curcumin is
restricted because of its moderate potency, poor solubility, low
bioavailability and rapid in vivo metabolism in humans [17]. Syn-
thesis of curcumin hybrids so as to circumvent their poor phar-
macological profiles is a promising approach and will open up new
avenues for the accessing highly active anticancer scaffolds.
Raghavan et al. developed a series of curcumin-quinolone hy-
brids (1, Fig. 2) from diversely substituted 3-formyl-2-quinolones
and vanillin, and tested their cytotoxicity against a panel of repre-
sentative cell lines [18]. Compound 1a emerged as the most potent
hybrid exhibiting IC50 values of 23.9, 36.2, 12.8 and 21.75 mM
against A-549 (lung), MCF-7 (breast), SKOV-3 (ovarian) and H-460
(lung) cell lines, respectively with selectivity against SKOV-3 cell
line. Compound 1a induced distorted cell morphology and induc-
tion of apoptosis in SKOV3 cell line. Further, the generation of
reactive oxygen species (ROS) proved to be the mechanisms of
Fig. 1. Estimated percentage of cancer deaths (both sexes) worldwide [2]. action against SKOV3 cell lines via inducing cycle arrest in the S and
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 181

Quinolone
O OH O OH
R H3C

N O OH N O OH
R1 1 O O
1a Curcumin
R = -H, -Cl, -F, -OCH3, -CH3
R1 = -H, allyl, propargly, benzyl

Fig. 2. Curcumin-quinolone hybrids (1) with the potent anti-cancer compound 1a.

G2/M phase. and androgen-independent human prostate cancer cell lines.


Sharma and co-workers investigated the cytotoxicity of 1H- Hybrid 3a with an N-ethyl-substituent exhibited the highest anti-
1,2,3-triazole tethered curcumin-isatin hybrids (2, Fig. 3) against a proliferative activity (IC50 ¼ 1.0 mM) against LNCaP, better than
panel of cancer cell lines [19]. SAR studies showed the dependence curcumin.
of activity on nature of ring and the presence of substituent at C-5 Wang and his team generated a library of curcumin-based hy-
position of isatin ring. The methoxy substituents on the phenyl ring brids (4, Fig. 5) by its molecular hybridization with a variety of
enhanced the anticancer activity of the synthesized hybrids, pharmacophoric units' viz. imidazole, oxazole, thiazole, pyrazole,
whereas the presence of halogen and nitro substituents reduced benzimidazoles and pyridine [21]. The anti-proliferative testing of
activity. Four of the promising hybrids were further evaluated for the synthesized hybrids against PC-3 (prostate), DU-145 (prostate),
tubulin inhibition studies. The most active compound 2a LNCaP (prostate) and HeLa (cervix) cancer cell lines disclosed
(X¼trimethoxy-phenyl and R ¼ H), exhibited potent activity having several promising candidates with IC50 < 3 mM which showed 5-to
IC50 values in the range of 1.12e5.67 mM against various tested 36-fold higher potency than curcumin. Two of the potent com-
cancer cell lines. Considerable inhibition of tubulin polymerization pounds viz. 4a and 4b, found to be non-cytotoxic toward normal
(IC50 ¼ 1.2 mM) against HCT-116 cells was observed for hybrid 2a. mammary epithelial (MCF-10A) cells at 1 mM concentration. Hybrid
Further, docking studies supported the significant cytotoxicity and 4a bearing benzimidazole moiety proved to be most active against
tubulin inhibition of compound 2a as it fits well at subunits of HeLa and PC-3 cells having IC50 values of 0.36 and 0.70 mM,
tubulin with stabilization via H-bonds, polar and Vander Walls respectively. Hybrid 4a inhibited PC-3 proliferation by arresting cell
interactions. cycle regulation at G1/G0 phase. From SAR point of view, imidazole
Chen et al. evaluated the anti-proliferative activity of curcumin- and benzimidazole moieties were observed to be favourable for
imidazol hybrids (3, Fig. 4) against PC-3 (human androgen- improving the anticancer potency.
independent prostate cancer), DU-145 (human androgen-
independent prostate cancer) and LNCaP (human androgen-
dependent prostate cancer) cell lines, using genistein as a refer- 2.2. Benzimidazole based hybrids
ence drug [20]. Most of the synthesized compounds exerted better
activity than curcumin and genistein against androgen-dependent Benzimidazole core has emerged as an important heterocyclic
scaffold because of its wide range of activities as well as synthetic

O O
H3CO Isatin
H3CO OCH3
X
R
O O OCH3
Curcumin OCH3
N N
N N N N N N
O O
O 2 2a
O
R = H, Cl, Br

H3CO

X=
H3CO OCH3 OCH3 OCH3
OCzH3 OCH3 OCH3
1 2 3 4 5 6 7

O S

Br NO2
Cl Br NO2
8 9 10 11 12 13 14

Fig. 3. Curcumin-isatin hybrids (2) with the potent hybrid 2a.


182 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Fig. 4. Curcumin-imidazol hybrids (3) with the potent antiproliferative hybrid 3a.

Fig. 5. Curcumin-benzimidazol hybrids (4) with the potent anti-proliferative hybrids 4a-b.

potential. Benzimidazole exhibits its structural resemblance with and TGI levels, respectively. The presence of a 4-chloro substituent
purines, because of which it can easily interact with various bio- at the phenyl ring on benzimidazole enhanced the anticancer ac-
molecules. Recent reports have shown the anti-cancer potential of tivity compared to the methyl, methoxy, or the hydroxyl groups.
substituted benzimidazoles while its hybrids with other heterocy- Further, in vitro interactions between 6a and human serum albumin
clic moieties have displayed improved anticancer activities [22]. (HSA) revealed the importance of hydrogen bonding and Vander
Singla et al. reported the synthesis and anticancer evaluation of Waals interactions in their interface. Further investigation revealed
benzimidazole-triazine hybrids (5, Fig. 6) against NCI-60 cell panel that the hybrid 6a induced cell cycle arrest at G0/G1 phase.
including nine tumour cell lines [23]. Among the evaluated hybrids, Sharma et al. [25] reported the synthesis and anticancer eval-
three compounds viz. 5a, 5b and 5c displayed prominent cell uation of benzimidazole-purine hybrids (7, Fig. 8) against the NCI-
growth inhibition at a concentration of 105 M against variety of 60 cell panel at a single dose of 10 mM concentration. The repre-
cancer cell lines. These compounds were further chosen for sentative compound 7a exhibited considerable inhibition towards
screening against a panel of 60 different tumour cell lines at 5-dose ovarian cancer, CNS cancer and colon cancer cell lines with GI50
concentration range viz. 104, 105, 106, 107 and 108 M. Hybrid values of 1.34, 2.00 and 3.16 mM, respectively. Also, compound 7a
5a showed good antitumor activity with growth inhibition (GI50) (MG-MID GI50 ¼ 18.12 mM) presented 1.25 fold greater activity than
values in the range of 3.56e19.0 mM against nine tumour subpanels 5-fluorouracil (5-FU), and was selective (IC50 ¼ 0.01 mM) towards
with the mean graph mid-point (MG-MID) GI50 value of 9.79 mM. Aurora-A kinase inhibition. Subsequently, QSAR model was devel-
Further, dihydrofolate reductase (DHFR) inhibition assay of the oped with good predictive ability for the affinity of this series of
promising hybrids 5a, 5b and 5c was performed to investigate their Aurora A kinase inhibitors with physicochemical descriptors. Mo-
mechanism of action. Hybrids 5a and 5c revealed excellent inhi- lecular docking studies explored the favourable binding of 7a with
bition potential while compound 5b was found to be ineffective the active site residues (His644, Asp622, Ser625 and Arg626) of
towards DHFR assay. The presence of -chloro substituent at the C-6 Aurora-A.
position of triazine significantly improved the inhibitory activity. Singla and co-workers reported the synthesis and anticancer
Benzimidazole-chalcone hybrids (6, Fig. 7) synthesized by studies of benzimidazole-triazine hybrids (8 and 9; Fig. 9) against
Kalalbandi and co-workers exhibited good to moderate anticancer the NCI-60 cell panel [26]. Four hybrids, 8a, 9a, 9b and 9c exhibited
activity against the NCI-60 cell panel [24]. Compound 6a, the pro- remarkable activity against leukemia cancer cell lines (SR) with GI50
totype of the series, displayed good antitumor activity (GI50 values of 731, 125, 539 and 31 nM, respectively. Moreover, these
values ¼ 0.38e3.13 mM) against nine tumour subpanel cell lines compounds also showed promising activity against renal cancer
(leukemia, non-small cell lung cancer, colon cancer, CNS cancer, cell lines RXF393 (GI50 < 750 nM). The presence of an aryl moiety
melanoma, ovarian cancer, renal cancer, prostate cancer and breast on the triazine ring positively influenced the anticancer activity of
cancer) with selectivity ratios of 0.79e1.53 and 0.47e1.69 at GI50 the hybrids. The strong binding affinity of hybrids with the bovine
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 183

Compound GI50 (μM)


no. leukemia non-small colon CNS Melan ovarian renal prostate breast MG
cell lung oma MID
5a 18.6 11.9 3.31 10.3 3.81 3.56 12.1 19.0 5.61 9.79
5b 3.71 2.56 2.76 1.86 2.70 2.41 1.89 2.75 2.58 2.58
5c 2.50 5.57 2.61 3.73 3.15 5.98 2.96 3.86 4.00 3.81
Fig. 6. Benzimidazole-triazine hybrids (5) with the potent compounds 5a-c.

on MCF-7 cells suggested that the hybrids induced apoptosis due to


increased production of ROS, elevation of Bax/Bcl-2 ratio, and
activation of caspase-3 and 7.
Sontakke et al. explored the anticancer screening of 2-anthryl
benzimidazole hybrids (11, Fig. 11) against the MCF-7 (breast) and
HL-60 (leukemia) cancer cell lines which led to the identification of
benzoyl substituted benzimidazole 11a that showed the highest
activity with IC50 values of 16.18 and 15.15 mM against MCF-7 and
HL-60, respectively. Molecular docking studies of 11a formed the
lowest energy (11.64 kcal mol1) stable complex with DNA [28].

2.3. Pyrimidine based hybrids


Fig. 7. Benzimidazole-chalcone hybrids (6) with the potent hybrid 6a.

Pyrimidine has widespread occurrence in various natural


serum albumin (BSA) was also established based on UV and fluo- products and displays significant pharmacological efficacy. The
rescence studies. pyrimidine derivative, 5-flouro-uracil (5-FU) has been extensively
Reddy et al. conjugated benzimidazole and pyrazole nuclei, and used for the treatment of various types of cancers via inhibiting
subjected the resultant hybrids (10, Fig. 10) to anti-proliferative thymidylate synthase activity in cancer cells [29]. Similarly, dia-
evaluation against three cancer cell lines viz. MCF-7 (breast), A- minopyrimidine based anticancer agents such as multi-targeted
549 (lung) and HeLa (cervical) [27]. Some compounds, especially drug Dasatinib, multi-targeted inhibitor Pazopanib along with
hybrids 10a, 10b and 10c exhibited superior growth inhibition (IC50 Crizotinib and erlotinib are used for the treatment of non-small cell
ranges 0.83e1.81 mM) as compared to 5-fluorouracil (IC50 ranges lung and pancreatic cancer and non-Hodgkin lymphoma [30].
2.13e4.16 mM) against the tested cancer cell lines. Mono- A series of pyrimidine-triazole analogues (12, Fig. 12) was syn-
substitution of halogens (F, Br and I) on the benzimidazole ring thesized by Ma et al. [31] and screened for their anticancer po-
noticeably increased the anticancer activity of these hybrids. The tential against four cancer cell lines. The presence of electron-
most potent compound 10a, exhibited the highest activity among donating groups, especially at C-4 position dramatically increased
the test compounds with IC50 of 0.83 mM against MCF-7 cell lines, the anticancer activity of the hybrids against the tested cancer cell
due to cell cycle arrest in the G1 phase of cell cycle as confirmed by lines. Compounds 12a, 12b and 12c emerged as the potent hybrids
flow cytometry analysis. The apoptotic effects of these compounds of the series having IC50 values 32, 35 and 42 nM, respectively
184 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Benzimidazol
R
N N
CH3 CH3
HN N HN N

N N N N

R2R1N N N N N N Purine
H H
7
7a
R = Allyl, butyl
NR1R2 = morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl,
piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl,
pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,
4-methylpiperazin-1-yl
Fig. 8. Benzimidazole-purine hybrids (7) with the potent compound 7a.

Fig. 9. Benzimidazole-triazine hybrids (8e9) with the potent compounds 8a, 9a-c.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 185

Fig. 10. Benzimidazole-pyrazole hybrids (10) with the potent compounds 10a-c.

MTT assay [33]. Substitution pattern (o-, m-, p-position) of phenyl


ring was examined to study its influence on activity profiles. The
results indicated the preference of p-substitution for better activ-
ities than corresponding o- and m-substituted derivatives against
the tested cancer cell lines. Further, a range of substituents at p-
position were evaluated with p-benzyl alkoxy group being most
appropriate in enhancing the anti-proliferative activity. The com-
pounds, 14a (IC50 ¼ 2.0 and 3.18 mM) and 14b (IC50 ¼ 4.01 and
2.04 mM) appreciably inhibited the MDA-MB-231 and MCF-7 cell
colony formation, respectively. It was further confirmed that 14a
Fig. 11. Benzimidazole-2-anthryl hybrids (11) with the potent compounds 11a. inhibited breast cancer cell proliferation by inducing cell-cycle ar-
rest at the G0/G1 phase.
Kumbhare and his team synthesized new pyrimidine-triazole
against B16-F10 cell line. The promising hybrid 12a induced hybrids (15, Fig. 15) and evaluated their anticancer activity
apoptosis by reducing the level of pro-caspase3 and increasing the against A-549 (lung), A-375 (skin) and MCF-7 (breast) cancer cell
level of active-caspase3 and p53. lines along with standard breast epithelial cells [34]. Generally, the
In another study, the anticancer evaluation of pyrazolo [3,4-d] incorporation of the triazole ring increased the selectivity of com-
pyrimidine (13, Fig. 13) hybrids revealed several potent compounds pounds against the MCF-7 cell line, while an opposite trend was
(GI50 < 5 mM) against the NCI 60-cell panel [32]. Compound 13a observed for the other two cell lines. Compounds 15a-d with
(IC50 ¼ 1.12 mM) showed comparable activity to doxorubicin against respective IC50 values of 3.0, 3.2, 2.52 and 2.12 mM exhibited
breast cancer cell line (MCF-7), and acceptable cytotoxicity promising activity against the MCF-7 cell line without showing
(GI50 ¼ 1.71e23.9 mM) against eight other subpanels. The hybrid toxicity to normal breast cells. Furthermore, inhibition studies on
13b, bearing a benzothiazole moiety exhibited promising activity ERK1/2, NF-kB and survivin demonstrated the apoptosis-inducing
(GI50 ¼ 1.79 mM) against the SNB-75 (CNS) cancer cell line. Flow ability of the hybrids.
cytometric analysis further established that compound 13b Koca et al. conducted anticancer evaluation of pyrimidine-
induced considerable cell cycle arrest at the G0/G1 phase, due to its thiourea hybrids (16, Fig. 16) against human bone osteosarcoma
ability to down-regulate cyclin D1 and up-regulate p27kip1 levels. (Saos-2) and human breast (MCF-7) cell lines along with their in-
Zhou and co-workers reported the anti-proliferative evaluation hibition studies against Heat Shock Protein 90 (Hsp90) [35]. Anti-
of 2,4-diaminopyrimidine-arylthiazole hybrids (14, Fig. 14) against cancer activity showed dependence on the latent functionalities on
two breast cancer cell lines (MDA-MB-231 and MCF-7) using the
186 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

H3C
R1
NH NH
CN CN
N N
OCH3
N S N S N
R2 N
HN N N HN N N
HN HN OCH3
O OH
N O N Pyrimidine OCH3
O
12 Triazole
12a
R1 = p-CH3, p-CH3, m-CF3, p-CH(CH3)2, p-
OCH3, o-OCH3, m-CF3, p-CH(CH3)2
R2 = 4-Isopropylphenyl , 3,4,5-
Trimethoxylphenyl, 3,4,5-Trimethoxylphenyl,
p-CH3, 4-Methylphenyl, 4-Methylphenyl
4-Bromophenyl, p-Br
CH3 CH3

H3C H3C

NH NH
CN CN
N N
OCH3
N S N N S N
HN N N HN N N
HN OCH3 HN Br
OH OH
N O OCH3 N O
12a 12a

Compound IC50 (μM)


no. EC-109 MCF-7 MGC-803 B16-F10
12a 21.34 20.97 7.03 0.032
12b 7.45 >64 19.29 0.035
12c >64 30.58 15.60 0.042
Fig. 12. Pyrimidine-triazole hybrids (12) with the potent compound 12a-c.

N Pyrazole
H
N N

N N O
N HN
H 13a
N N Pyrimidine
R
N N O

HN N
R = H, Cl
13 R4 H
N N
R4 = cyclohexyl, 3-Cl-phenyl, 4-Cl-3-CF3-phenyl,
2-Cl-phenyl N N O

HN
13b

Cl
Fig. 13. Pyrimidine-pyrazolo hybrids (13) with the potent compound 13a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 187

N H
H N N
R N
S N
14
R = 2-Cl, 3-Cl, 4-Cl, 2-BnO- 3-BnO, 4-BnO, 4-F, 4-Br, 4-BnCH2O, 4-Bn(CH2)2O, 4-Bn(CH2)3O

Pyrimidine
Thiazole N H H
H N N H N
N N N N
Bn
Bn S N S N
O O
14a 14b

Fig. 14. Diaminopyrimidine-thiazole hybrids (14) with the potent compounds 14a-b.

N
N N
O
N
N
S
HN
N N R
15
R = 4-FC6H4, 2,4-FC6H3, 3-CF3C6H4, (3-Cl-4-FC6H3), Cyclopropane, Cyclohexane, CH2-4-OCF3C6H4,
4-SCF3C6H4, 5(CF3)-1,3,4-thiadiazole, 4-F-benzothiazole, morpholine
Benzothiazol
N N
N N Pyrimidine N N
O O OCF3
N F N
N N
S S
N HN HN
N N N
15a
F 15b

N N
N N N N
O O
N F N
N N
S S S
HN HN
N N 15d N N CF3
15c SCF3 N N

Compound IC50 (μM)


no. MCF-7 A549 A375 MCF10A
15a 3.0 4.45 6.02 22
15b 3.2 4.62 6.02 26
15c 2.52 4.97 4.67 25
15d 2.12 5.48 4.7 29.33
Fig. 15. Pyrimidin-benzothiazol hybrids (15) with the four potent hybrids 15a-d.

the synthesized hybrids. Compound 16a emerged as the most 2.4. Coumarin based hybrids
potent compound of the series with IC50 of 7.68 and 6.51 mM against
Saos-2 and MCF-7 cell lines respectively. Further, gene expression Coumarin is considered as a privileged framework because of its
was investigated through microarray examination on MCF-7 cell abundance in naturally occurring products with diverse pharma-
lines. SAR studies suggested the role of side groups and their cological profiles such as lipid lowering agents, radical scavangers,
orientation on the increased anticancer activity. Molecular docking HIV integrase inhibitors as well as anti-invasive compounds
studies also supported the strong affinity of these hybrids to bind because of the inhibition of matrix metalloproteases (MMPs) [36].
and block Hsp90 protein.
188 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Pyrimidine Br
O O O O
R
N N N N N N
H H H H
O N Ph O N Ph
16 16a Acyl-urea

R= H3C H3CO F

CH3
O
Cl Br
H2N

Fig. 16. Pyrimidinyl acyl-urea hybrids (16) with the potent compound 16a.

O O
O O
O
N
R N
H R
17 18
R = H, Cl, Br, OH
Coumarin
Indole O
O Br O
OH
O

N
N O H
H
O 18a Br
19
Fig. 17. Indole-coumarin hybrids (17, 18 and 19) with the potent cytotoxic compound 18a.

Coumarin derivatives target a number of pathways in cancer such cycle arrest in the G2/M phase.
as kinase inhibition, cell cycle arrest, angiogenesis inhibition, heat Galayev et al. performed the conjugation of 7-hydroxy-8-
shock protein (HSP90) inhibition, telomerase inhibition, antimitotic methyl-coumarins (20, Fig. 18) with a variety of pharmacophores
activity, carbonic anhydrase inhibition, monocarboxylate trans- viz. pyrimidine, indole, pyran, pyrazole, tetrazolo [1,5-a]pyrimidine,
porters inhibition, aromatase inhibition and sulfatase inhibition 2-oxo-1,2-dihydropyridine, dihydropyrazolo [3,4-b]pyridine and
[37]. pyrimido [1,2-a]benzimidazole, and tested their cytotoxicity
Three series of coumarin-indole hybrids (17e19, Fig. 17) were against the NCI-60 cell panel [39]. Anticancer screening data
synthesized and tested for their in vitro cytotoxicity against human revealed the influence of nature of substituent present at C-6 po-
breast adenocarcinoma (MCF-7) and normal cell lines using MTT sition of indole ring as well as at C-3 and C-4 position of coumarin
assay and compared with that of the standard drug, vincristine [38]. on the anticancer activity. SAR studies recognized indole-coumarin
Halogen-substituted hybrids showed good in vitro cytotoxic activity hybrid 20a, with fluoro substituent at C-6 position of indole ring,
against MCF-7 (breast cancer) cells as compared to their un- having high anti-mitotic activity against leukemia (GI50 ¼ 3.08 mM)
substituted or hydroxy-substituted analogues. SAR studies of syn- and melanoma (TGI ¼ 9.71 mM) cancer cell lines. The same com-
thesized indole-coumarin hybrids revealed enhancement in anti- pound exhibited highest correlation among synthesized com-
tumour potency with the introduction of a bromine substituent pounds, at GI50 level with glycopeptide antitumor antibiotic
on coumarin, which could be attributed to the increase in lip- Bleomycin [PCC (Pearson correlation coefficients) ¼ 0.595] and dual
ophilicity that favours the passage through bio-membranes. Com- inhibition of topoisomerase I and II, Aclacinomycin A (PCC ¼ 0.636).
pound 18a, with high lipophilicity and good ability to form Three series of coumarin-pyrazoline hybrids (21e23, Fig. 19)
hydrogen bonds, was recognized as the most potent analogue were synthesized and tested for their anti-proliferative activity
(IC50 ¼ 7.4 mM) among the series. In silico docking revealed against carcinoma hepato-cellular (HepG2) cell line [40]. Substi-
favourable binding of potent hybrids with the Bcl2. Also, flow tution pattern on pyrazoline ring influenced the anti-proliferative
cytometric cell cycle analysis of 18a revealed apoptosis due to cell activity. Hybrids with lipophilic moieties and without N-1
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 189

CH3 CH3
Indole
HO O O HO O O

R1
NH R2 NH CH3

R3
20 20a Coumarin
F
R1 = H, CH3, (CH2)3, CH2)4
R2 = CH3, (CH2)3, CH2)4, (CH2)2CH3, CH2)3CH3
R3 = H, 6-F, 7-CH3, 5-Br

Fig. 18. Coumarin-indole hybrids (20) with the potent anticancer compound 20a.

Fig. 19. Coumarin-pyrazoline hybrids (21e23) with the potent compounds 21a, 22a and 23a.

substituent on the pyrazoline ring showed appreciable activity. The for their in vitro antitumor activity against the NCI 60-cell panel
potent compounds viz. 21a, 22a and 23a with IC50 values of 10, 15 [41]. SAR of anti-cancer activity data revealed that the nature of
and 18 nM, respectively showed reasonable reduction in telome- substituent present at C-3 and C-6 position of imidazo[1,2-a]pyr-
rase activity (61.7e78%). Furthermore, most potent hybrid, 21a azine influenced the biological potency. The symmetrical diarylated
screened for apoptosis induction displayed apoptosis in a dose hybrids 24a-b showed potent anticancer activity towards most of
dependent manner. the cancer cell lines along with good lipophilicity and drug
Novel imidazo [1,2-a]pyrazine-coumarin hybrids (24, Fig. 20) bioavailability. Compounds, 24a and 24b displayed excellent anti-
were synthesized via Suzuki-Miyaura cross coupling and screened cancer activity with GI values of 90% against renal (A-498) and 93%
190 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Fig. 20. Coumarin-pyrazine hybrids (24) with the potent compounds 24a-b.

Fig. 21. Coumarin-triazole hybrids (25) with the potent compounds 25a.

against breast (MDA-MB-231/ATCC) cancer cell lines. The most benzimidazoles and indole rings on the main core improved the
potent hybrid, 24b exhibited 17% toxicity at a concentration of anticancer activity. Hybrid 25a, induced cell death via triggering
100 mM to normal human embryonic kidney cells (Hek293) in the early apoptosis. Significantly, anticancer properties of hybrid 25a in
MTT assay. Molecular docking studies were in good agreement with HepG2 cells could be linked with its inhibition of 5-lipoxygenase
inhibitory potential of hybrid, 24a. (5-LO).
The coumarin-triazole hybrids (25, Fig. 21), synthesized by
Kraljevic and co-workers using Cu-catalyzed azide-alkyne cyclo- 2.5. Pyrazole based hybrids
addition strategy, emerged as prospective anti-proliferating hy-
brids against A-549 (lung) and HeLa (cervical) carcinoma cell lines Abd El-Karim and co-workers [43] explored the synthesis of
with IC50 < 30 mM [42]. 7-methylcoumarin-1H-1,2,3-triazole-2- novel pyazole-benzofuran hybrids (26, Fig. 22) and their in vitro
ethyl-benzimidazole 25a displayed highest cytotoxicity among anticancer evaluation against the NCI 60-cell panel on a single dose
synthesized hybrids with IC50 value of 0.90 mM against HepG2 concentration (105 M). The analogues with 3-furano-isoxazole
(hepatocellular) cell line, and a selectivity index of 50, but some- and 3-furano-N-acetylpyrazoline rings resulted in hybrids with
what toxic to normal fibroblasts WI38 and 3T3 (IC50 ¼ 45.33 mM). broad spectrum anticancer activities. The most potent hybrid 26a
The introduction of fused heterocycles such as benzothiazole, with GI50 ranging between 1.00 and 2.71 mM displayed a
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 191

Pyrazole
R N O
N N O
N H N

O N N
O N N
26
Benzofuran 26a

R = 4-Cl-C6H4-, Cyclohexyl, 2-Pyrrolyl, 2-Furyl

Fig. 22. Pyrazole-benzofuran hybrids (26) with the potent anticancer hybrid 26a.

noteworthy growth inhibitory activity pattern against leukemia better inhibitory effects on mushroom tyrosinase than the positive
(CCRF-CEM, MOLT-4), breast cancer (HS 578T, T-47D), lung cancer control. Among these, compound 27a exhibited promising anti-
(HOP-92), CNS cancer (SNB-75), ovarian cancer (IGROV1), colon cancer activity (IC50 ¼ 0.9e2.2 mM) towards all tested cell lines,
cancer (HCC-2998), melanoma (SK-MEL-2) and renal cancer whereas hybrid 28a (IC50 ¼ 4.72 mM) displayed three folds greater
(786e0, RXF 393). Furthermore, 26a proved to be a good inhibitor tyrosinase inhibition than kojic acid (IC50 ¼ 12.42 mM). SAR analysis
of c-Src at10 mM. Molecular docking studies of synthesized hybrids disclosed the importance of pyrazoline in the anticancer activity as
were performed with binding site of Src kinase with 26a displaying its absence decreased the activity significantly against all tested
excellent fitting with these binding sites. Additionally, hybrid 26a cancer cell lines. To investigate the interactions of these compounds
fulfilled Lipinski's rule of five along with ADME profile making it a with tyrosinase enzyme, molecular modelling studies were per-
promising scaffold for future amendments. formed, the results of which agreed well with the in vitro tumour
Qin et al. tested the inhibitory effects of pyrazoline-benzofuran cell inhibitory activity.
hybrids (27 and 28, Fig. 23) on the diphenolase activity of mush- A series of pyrazole-triazole hybrids (29, Fig. 24) were synthe-
room tyrosinase along with their anti-proliferation studies against sized by Reddy and co-workers displayed remarkable cell growth
a panel of cancer cell lines [44]. Four compounds exhibited the inhibition against four human tumour cell lines viz. HT-29 (colon),

R N S Benzofuran
N
NH2 Pyrazole
O
R4 R1 N
S
N
R2
NH2
R3
27
O
27a
N
R=
O ,
O
R1 = H, OCH3
R2 = H, OCH3; R3 = N(CH3)2, H, OCH3
R4 = H, OCH3

R N O O
N N
HN Cl O
N
R4 R1 HN
Cl
R2
R3 28a
N
28
Fig. 23. Pyrazole-benzofuran hybrids (27 and 28) with the potent anticancer hybrids 27a, 28a.
192 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

R Triazole
F
O
N O OCH3
N N
R1 N
N OCH3
N N
N N
N
29 Pyrazole
29a

R = H, F, Cl, OMe, 3,4,5-OMe


R1 = F, Cl, CF3, OMe, 3,4-OMe, 3,4,5-OMe

Cl
H3CO
O OCH3
N O OCH3
N N
OCH3 N
N OCH3
N
N
N N
N
29b 29c

Compound IC50 (μM)


no. HT-29 PC-3 A549 U87MG
29a 2.54 5.87 2.13 3.76
29b 2.42 3.71 1.93 0.86
29c 1.78 3.52 2.24 0.97
Fig. 24. Pyrazoloetriazole hybrids (29) with the potent compounds 29a-c.

PC-3 (prostate), A549 (lung) and U87MG (glioblastoma), as exem- functionalized pyrazoles (30). The anti-proliferative evaluation of
plified by 29a-c which showed superior cytotoxic activity the synthesized compounds against Bcap-37, MGC-803 and SGC-
(IC50 ¼ 0.86e3.72 mM) to the reference drug (5-FU) [45]. Flow 7901 cell lines disclosed four potential anticancer compounds with
cytometry analysis indicated that these compounds induced cell IC50 < 7.5 mM for the MGC-803 cell line. The representative com-
cycle arrest at the G1 phase. For U87MG cells, the synthesized hy- pound 30a displayed superior activity to 5-FU, and showed the
brids induced apoptosis via mitochondrial pathway through up- following toxicity order: MGC-803 (IC50 ¼ 3.01 mM) > SGC-7901
regulation of pro-apoptotic (Bax) and down-regulation of anti- (IC50 ¼ 8.30 mM) > Bcap-37 (IC50 ¼ 10.50 mM). Interestingly,
apoptotic (Bcl-2) genes. incorporation of a pyrimidine ring in this class of compounds
Novel pyrazole-pyrimidine hybrids (31, Fig. 25) were developed decreased their anti-proliferative activity. The most potent
by Shi et al. [46] using a base induced cyclization reaction of the pyrazole-pyrimidine analogue (31b) with an IC50 value of 7.14 mM

Pyrazole
O Pyrimidine O
O N N N
HN O HN N
N N N N
R N O O
H R N N N
NH2 H
O NH2 31a
30a O
30 31

O
O O
R = O
O O
O O O O

Fig. 25. Functionalized pyrazole (30) and Pyrazoloepyrimidine hybrids (31) with potent compounds 30a and 31a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 193

displayed lower activity than 5-FU. Flow cytometric analysis of 30a improvement in the cytotoxicity of both compounds was observed
on MGC-803 cell lines showed cell arrest in S phase. The docking with respect to the parent phenol 32, which could be attributed to
studies of 30a into the active site containing ASP 254 simulated better cellular uptake and subsequent metabolism.
binding of compound into catalytic subunit of tolmerase (TERT). Tang et al. described the synthesis and screening of another
series of 6-aryl-indenoisoquinolone hybrids (35, Fig. 28) as dual
inhibitors of oestrogen receptor ERa and vascular endothelial
2.6. Quinoline based hybrids
growth factor receptor-2(VEGFR-2) [49]. Most hybrids exhibited
good inhibitory activities towards ERa with exceptional anti-
Quinoline-stilbene hybrids (32, Fig. 26) developed by Srivastava
proliferative activities against human endometrial cancer cell line
et al. were evaluated for their anti-proliferative activity against
(Ishikawa), human breast cancer cell lines (MDA-MB-231 and MCF-
various cancer cell lines [47]. Among twenty five synthesized
7) while some of them exhibited potent VEGFR-2 inhibitory activ-
compounds, three cis-compounds (32a-c) exhibited potent anti-
ity. SAR indicated reduction in anti-proliferative activity with in-
proliferative activity with IC50 less than 4 mM being two folds
crease in length of side chain against MCF-7 and MDA-MB-231 cell
more selective against cancer cells as compared to non-cancerous
lines. Compound 35a exhibited the strongest inhibition for both
cells. The trans-hybrid 32d, showed amazingly high activity
targets, and was able to inhibit the activation of VEGFR-2 and
against MDA-MB 468 breast cancer cells (IC50 ¼ 0.12 mM). Data from
signaling transduction in the Raf-1/MAPK/ERK pathway in MCF-
flow cytometry and immune fluorescence microscopy confirmed
7 cells.
that 32d resulted in significant DNA damage with the consequential
cell cycle arrest in the S-phase and eventual apoptosis. The cis-
compound, 32a with an IC50 of 6.01 mM against MCF-7 caused 2.7. Quinone based hybrids
prolonged cell cycle arrest at the spindle checkpoint step, which
ultimately resulted in cell death via apoptosis. In silico molecular The conjugation of anthraquinone and chalcone pharmaco-
modelling studies were in agreement with experimental data and phores (36, Fig. 29) was reported by Markovi and co-workers [50].
predicted that the compound 32a binds in the same cavity where Three hybrids 36a-c with encouraging anticancer activity
podophyllotoxin binds. (IC50 ¼ 2.73e2.36 mM) equivalent to cisplatin against HeLa (cervix
The cytotoxic evaluation of indeno-isoquinoline hybrids (34, cancer) cells and low cytotoxicity for MRC-5 (non-cancerous) cell
Fig. 27) resulted in several potent derivatives with GI50 line was identified. These hybrids showed selective cytotoxic effect
values < 10 nM against a variety of human cancer cell lines [48]. especially on HeLa cells promoting accumulation of cells in the S
Compounds 34a and 33b with GI50 values < 0.01 mM showed and G2/M phase and kills cancerous cells by inducing caspase-
promising activity against MCF-7 (breast), DU-145 (prostate), dependent apoptosis. From SAR point of view, the hybrids with
SN12C (renal) and SF-539 (CNS) cancer cell lines. A noteworthy the two enone units displayed higher anticancer activity than those

R2
R3 R1 R1 = H, CF3
R2 = H, CF3
R4 R3 = H, F, CF3
R4 = H, CF3
R5
R5 = H, OCH3, -OCH2O-
R6 = H, Cl
R6 N Cl

32

Stilbene CF3 CF3


CF3 F

H3CO H3CO
N Cl
N Cl N Cl N Cl 32d
32a Quinoline 32b 32b

Compound IC50 (μM)


no. HeLa MCF7 MDA-MB231 MDA-MB468 184B5
32a 2.85 3.53 3.75 3.70 6.15
32b 3.03 2.78 3.28 3.91 5.58
32c 2.60 4.47 2.77 4.98 5.31
32d >50 15.13 >50 0.12 38.45
Fig. 26. Quinolino-stilbene hybrids (32) with the potent hybrids 32a-b.
194 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Fig. 27. Indenoisoquinoline prodrugs (34) with the two potent antiproliferative hybrids 34a-b.

Fig. 28. 6-Aryl-indenoisoquinolone hybrids (35) with the potent anti-breast cancer hybrid 35a.

with a single enone unit without any noticeable influence of the on the quinazoline ring and methoxy or chlorine functionalities on
nature and position of the substituents. the isatin moiety enhanced the anticancer activity whereas com-
Jiang and co-workers generated a new series of tricyclic pound with thiophene functionality at quinazoline ring proved to
quinone-based hybrids (37, Fig. 30) by coupling its nucleus with be less potent.
pyran and lactone moieties, and tested their anticancer activity Qiao et al. explored the anticancer potential of novel quinazo-
against various cancer cell lines [51]. Most of the synthesized hy- line-1,3,4-oxadiazole hybrids (40, Fig. 32) against A549 (lung),
brids exhibited significant anticancer activity, as exemplified by 36a MCF-7 (breast) and HeLa (cervix) cancer cell lines [45,53]. Hybrids
with IC50 ¼ 0.66 mg/mL against KB cells which is comparable with bearing substituted aromatic rings displayed superior activity with
standard drug, vincristine (IC50 ¼ 0.46 mg/mL). respect to their phenyl analogues. SAR suggested the dependence
of anticancer potential on the nature and position of substituent on
2.8. Quinazoline based hybrids phenylacetic acid. The presence of electron releasing substituents
(CH3 or OCH3) increased VEGFR2 inhibitory activity more than
Alafeefy and co-workers synthesized a series of quinazoline- electron withdrawing substituents (such as F, Cl, Br). Compounds
indole hybrids (39, Fig. 31) via intramolecular condensation reac- with a methoxy substituent at m- or p-position of phenylacetic acid
tion of the corresponding benzamides (37) [52]. The antitumor displayed higher antitumor activity than at o-position against MCF-
evaluation of both sets (38 and 39) disclosed three compounds 38a 7. Furthermore, a comparison of halogen group (F, Cl, Br) at the p-
(IC50 ¼ 1.86 mg/mL), 38b (IC50 ¼ 4.42 mg/mL) and 39a position on phenylacetic acid revealed the potency order of VEGFR2
(IC50 ¼ 1.46 mg/mL) with potent anticancer activity against the Daoy inhibitory activity as: F < Cl < Br. Compound 40a emerged as the
(medulloblastoma) cancer cell line. The presence of a p-tolyl group most potent compound (IC50 ¼ 0.230 mM for MCF-7, 0.38 mM for
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 195

O
O
Anthraquinone
R
O
O O
O

Chalcone
36 36a
O
O
R = H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-F, 4-F, 2-NO2

O CH3 O NO2

O O
O O

36b 36c
O O

Compound IC50 (μM)


no. HeLa LS174 A549 MRC-5
36a 2.41 4.56 26.20 33.57
36b 2.36 3.13 29.05 41.87
36c 2.73 6.44 28.84 48.76
Fig. 29. Anthraquinone-chalcone hybrids (36) with the three potent anticancer compounds 36a-c.

O Lactone
R O
N O O O
H
N N O O
H H
O N
H
O O
Pyran
37 O
37a

Quinone

N
R= N N
N N O O
O Boc

Fig. 30. Quinone-pyran-lactone hybrids (37) with the potent anticancer compound 37a.

A549 and 0.32 mM for HeLa) of the series with comparable activity 2.9. Pyridine based hybrids
to the positive control Tivozanib. In silico docking simulations
further disclosed the importance of four amino acids (Lys868, Pyridine constitutes imperative class of heterocycles with
Cys919, His1026 and Asp1046) in the host-guest relationship be- interesting anticancer profiles. Sorafenib, Regorafenib, Vismodegib
tween 40a and VEGFR through pp interactions and hydrogen and Crizotinib are few important clinically approved pyridine-
bonding. containing anticancer drugs [54]. Pyridine-based hydrazone has
196 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

R
R

O
NH O
N NH
N N
H O N
NH O
N Ar
O Ar
39
38 R = H, Cl, Me, MeO, NO2
R = H, Cl, Me, MeO, NO2 Ar = 4-MeC6H4, thiophen-2-yl
Ar = 4-MeC6H4, 4-NO2C6H4
Cl O Cl Isatin
Quinazoline

O O O
N NH NH NH
N N
N N N
H O H O O
NH NH N
O O CH3
CH3 CH3 39a
38a 38b

Compound IC50 (μM)


no. Daoy UW228-2 Huh-7 Hela MDA-MB23
38a 1.86 6.87 3.20 6.52 5.95
38b 4.42 5.82 4.6 8.09 10.89
39a 1.46 5.70 3.76 8.60 4.80
Fig. 31. Quinazoline-isatin hybrids (38 and 39) with the potent cytotoxic hybrids 38a-b and 39a.

N N Oxadiazole
O O N
N
O O
N N
R O
N N
40 40a O
Quinazoline
Br O

Cl NO2 F OCH3 Br
R=

H3CO OCH3 Cl H3CO F


Cl Br

OCH3

CH3 F OCH3 Cl Br NO2

Fig. 32. Quinazoline-oxadiazole hybrids (40) with the potent analogue 40a.

shown to inhibit the growth of tested cancer cell lines at the NCI, (42, Fig. 33), prepared from corresponding hydrazone (41), for their
USA with no apparent animal toxicity. Pyridine-tethered com- anticancer potential against human liver (HepG2) cancer cell line
bretastatin-A4 hybrids have shown potent anticancer activities [56]. Three compounds 41 and 42a-b of the series showed superior
with the most potent compound displaying modest activities activity (IC50 ¼ 8.0, 8.4 and 10.3 mM) compared to the positive
against A549 lung cancer, MDA-MB-231 breast cancer and Hela control doxorubicin. The sulfonamide and pyridine moieties posi-
cervical cancer cell lines [55]. tively influenced the anticancer activity. Additionally, these potent
Ghorab et al. screened a series of pyridine-sulfonamide hybrids compounds showed interesting radio-sensitizing activity when g-
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 197

O
H H2N O
N O O
N
O N N Ar
HN CN
O S O Ar CN HN O CN
O S O
41 42
Cl
Cl

O O
H2N O H2N O

N N N N
CH3
O HN O CN
HN O CN
O S O O S O
Pyridone
Sulfonamide
42b
42a
Cl Cl

Ar = C C O
O H H
Cl O O NO2

Cl N NO2

Compound IC50 (μM)


no. HepG2
41 8.0
42a 8.38
42b 10.3
Fig. 33. Pyridone-sulfonamide hybrids (42) with the potent compounds 42a-b and 41.

radiations combine with these potent compounds (41 and 42a-b). Br


R1
Molecular docking studies further revealed strong binding pro-
pensities of the potent compounds with the human carbonic A
anhydrases IX. R2 N
Ren and co-workers reported a new series of pyrimidine- N N N N S
S
thiazolinone hybrids (43, Fig. 34), and evaluated as potential
EGFR and HER-2 kinase inhibitors and in tumour cell anti- N N
proliferation [57]. Most of the synthesized hybrids displayed potent 43a
43 O O
anticancer (IC50 ¼ 0.099e19.62 mM) and EGFR/HER-2 inhibitory
activities (IC50 ¼ 3.26e20.33 mM) with no toxicity toward 293T.
Compound 43a exhibited the highest inhibition (IC50 ¼ 0.009 mM) R1 = H, CH3, OCH3, F, Cl, Br
against EGFR, and potent anti-proliferative activity against B16-F10,
R2 = N
HeLa and MCF-7 with IC50 values of 0.09, 0.29 and 0.56 mM
respectively. Biological evaluation data demonstrated that thiazo- N N
linone, pyridine and dihydropyridine rings have vital roles in EGFR Fig. 34. Pyridine-thiazole hybrids (43) with the potent anticancer hybrid 43a and 43b.
and HER-2 inhibitory activities.
In another study, Kamal and co-workers utilized the Cu-
promoted azide-alkyne cycloaddition (CuAAC) reaction methodol- the tested hybrids, three compounds 44a-c exhibited considerable
ogy to prepare pyridine-triazoles (44, Fig. 35) and tested for their cytotoxic activity (IC50 ¼ 0.1e4.1 mM) by apprehending the cell
cytotoxicity against Ht-29, DU-145 and A549 cell lines [58]. Among cycle at the G2/M phase resulting in apoptosis. The tubulin
198 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

O
N
N
N R = 4-OMe, 3,4-diOMe, 3,5-diOMe, 3-OPh, 4-F
N NH R
R1 = 4-OMe, 3,4-diOMe, 3,5-diOMe, 4-F

R1 44

O Triazole O O

N N N
N N N
O O O
N N N NH N
N NH N NH
O
Pyridine O
44c
F 44a F 44b F

Compound IC50 (μM)


no. HT-29 DU-145 A549 HEK-293
44a 3.7 3.1 4.1 64.3
44b 3.1 3.0 3.9 75.2
44c 0.2 0.1 1.1 59.6
Fig. 35. Pyridine-triazole hybrids (44) with the potent cytotoxic hybrids 44a-c.

polymerization assay and immune-fluorescence analysis showed Shah and his team performed the conjugation of pyridine with
that these compounds effectively inhibited microtubule assembly sunitinib (an antitumor hybrid targeting tyrosine kinases), and
in human prostate cancer cells (DU-145). The authors also tested the cytotoxicity of resultant hybrids (46, Fig. 37) against
demonstrated favourable binding of 44c in the colchicine binding panel of cancer cell lines [60]. Prototype of series 46a
site of tubulin in silico. (IC50 ¼ 3.21 mM) exhibited superior anticancer activity to sunitinib
The same authors in another study coupled the pyridine and (IC50 ¼ 6.98 mM) against MDA-MB-231 through apoptosis induc-
chalcone motifs to generate hybrids 45 (Fig. 36) [59]. The cytotox- tion. This was interceded via an increase in p53 level and down-
icity evaluation of resultant hybrids against HeLa (cervical), A549 regulation of phospho-signal transducer and activator of tran-
(lung), MCF-7 (breast) and HCT116 (colon) cell lines revealed two scription 3 (STAT3) and its phosphorylation. The importance of the
potent compounds (45a and 45b) with IC50 values ranging from hydroxyl group at C-5 position in the anticancer activity was
0.51 to 1.29 mM. Flow cytometry results established that com- further established.
pounds 45a-b triggered G2/M cell-cycle arrest in A549 cell line. Liu et al. reported the synthesis of pyridine-indazole hybrids (47,
Moreover, 45a (IC50 ¼ 1.34 mM) displayed significant inhibition of Fig. 38) as potent inhibitors of threonine tyrosine kinases (TTK)
tubulin polymerization with respect to the standard drug, noco- [61]. Compound 47a displayed potent inhibition of a panel of 278
dazole (IC50 ¼ 2.64 mM) which was further supported by docking kinases, and was the most efficacious in an HCT 116 tumour xeno
studies. graft model (77% TGI at 35 mg/kg PO). Compound 47a impressively

Fig. 36. Pyridine-indole hybrids (45) with the potent cytotoxic hybrids 45a-b.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 199

Fig. 37. Pyridinol-Sunitinib hybrids (46) with the potent cytotoxic compound 46a.

OH
R''
N

O Pyridine Indazole
R''' O
N
H N
N N
H H N
N N
47 H
47a

N * *
R'' = * * * *
* F N N
F N
Cl

* N N
* * * * * *
N N N
N N N

OH OH
O O
R''' = O
N N
N N N
* *
* * *

Fig. 38. Pyridine-indazole-5-carboxamides hybrids (47) with the potent anticancer hybrid 47a.

attenuated the growth of BT-474 (GI50 ¼ 0.015 mM), MDA-MB-231 2.10. Triazole based hybrids
(GI50 ¼ 0.070 mM), MCF-7 (GI50 ¼ 0.015 mM), OV-90
(GI50 ¼ 0.030 mM), SKOV-3 (GI50 ¼ 0.017 mM) and TOV-21G A suite of 1,2,4-triazolo-quinoxalines analogues (48, Fig. 39)
(GI50 ¼ 0.016 mM). The authors demonstrated a rational separa- were designed, synthesized and tested for their anticancer poten-
tion of effects between TTK potency, human CYP and hERG activity tial against the NCI-60 cell panel by Issa et al. [62]. A representative
(1000-fold) for this compound. compound, 48a showed effective activity toward non-small cell
200 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Triazole
Cl
R1
N
N
N N
N N

N
N

48 Quinoxaline
48a
R1 = H, CH3, 2-ClC6H4, 4-NO2C6H4, CH2CH2COOH, 2-COOHC6H4, COOEt, CH2COOEt

Fig. 39. Triazole-quinoxaline hybrids (48) with the potent compound 48a.

lung cancer HOP-92, prostate cancer PC-3, renal cancer A498, HCT- active compound of series (49a) exhibited respective GI50 values of
15, leukemia SR, colon cancer HCT-116, CNS cancer U251, NCI-H460, 52.5 and 41.3 mg/mL for HCT-15 and NCI-H226 cell lines. These
melanoma LOX IMVI and breast cancer MDA-MB-468 cell lines with hybrids were also tested for non-cancerous human embryonic
GI50 values of 3.91, 3.45, 3.49, 1.96, 5.18, 3.69, 1.80, 5.19 and 5.55 mM, kidney cells HEK-293. None of the hybrid displayed significant ef-
respectively. Generally, the hybrids with chloro-substitution, irre- fect on HEK-293 cells indicating their selectivity towards cancerous
spective of its position, showed higher potency against most of the cells.
cancer cell lines investigated. The triazole-dibenzodiazipinone hybrid 50a (50, Fig. 41) syn-
Novel 2,3-triazole-benzoxepine hybrids (49, Fig. 40) synthesized thesized by Kumar et al. displayed potent tumour growth inhibition
by Kuntala et al. were evaluated for their cytotoxicity against HCT- in five human cancer cell lines [64]. Most potent compound 50a
15 (colon) and NCI-H226 (lung) cancer cell lines [63]. The most exhibited IC50 values in range from 0.71 to 7.29 mM for various

Benzoxepine
R1
O O O
R3 O
O
R2
N N N
Cl N N Triazole
Cl N
49 49a

R1 = Me, H
R2 = Me, H, Cl
R3 = C6H4CH3-P, Ph, CH2O(quinolin-8-yl), CH2O(2-oxo-2H-chromen-7-yl),
CH2O(4-methyl-2-oxo-2H-chromen-7-yl)

Fig. 40. Triazole-benzoxepine hybrids (49) with the potent compound 49a.

Triazole
NH
NH
N N N
N N N
N
O N
O
50
50a
R Dibenzodiazipinone

R = H, 4-NO2, 3-NO2, 4-F, 2-F, 3-F, 4-Cl, 3,4,5-trimothoxy, 2,5-dimethoxy,


2,3,-dioxole, 2-trifluoromethoxy
Fig. 41. Triazole-dibenzodiazipinone hybrids (50) with the potent antiproliferative hybrid 50a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 201

cancer cells. In addition, 50a induced cell cycle arrest in the G2/M [69]. Cyototoxic data confirmed that electron withdrawing groups
phase for both A549 and MDA-MB-231 cell lines, and induced (halogen or nitro) either at isatin or phenyl ring was not encour-
apoptosis through drop in mitochondrial membrane potential aging whereas grafting electron donating groups (methyl or
(DJm) and an increase in ROS generation. methoxy) at isatin or phenyl ring were found to result in
enhancement of cytotoxcity. Among tested compounds, hybrid 53a
having methyl group on isatin ring and three methoxy group on
2.11. Isatin based hybrids phenyl ring emerged as an excellent inhibitor against all the
tumour cell lines and showed toxicity against REH (IC50 ¼ 0.5 mM)
Isatin is one of the most promising classes of heterocyclic sys- and K562 (IC50 ¼ 2 mM). Flow cytometric analysis revealed that 53a
tem with interesting pharmacological activities and well toleration induced apoptosis without arresting the cell cycle.
in humans. Currently, an isatin-based triple angio-kinase inhibitor New isatin-dehydroepiandrosterone hybrids (54, Fig. 44)
BIBF1120 II, is in phase III clinical trials in non-small cell lung cancer showed good antitumor activities against tested cancer cell lines
[65]. Further, Sunitinib, III, (Sutent) is a multikinase inhibitor tar- [70]. Synthesized hybrids exhibited better inhibitory activities
geting VEGFR-1, VEGFR-2, PDGFRb and c-Kit and was approved by against all screened cells at 20 mg/mL as compared to the positive
FDA for the treatment of gastrointestinal stromal tumors (GIST) and control 5-FU. The prototype 54a of the series displayed consider-
advanced renal cell carcinoma (RCC) [66]. Literature rationale has able inhibition activity (IC50 ¼ 5.97 mM) against BEL-7402/5-FU cell
shown the emergence of isatin hybrids viz. isatin-benzothiazole, line. It also exhibited IC50 values of 16.22, 13.90 and 14.83 mM
isatin-chalcone, isatin-thiazoline, isatin-benzimidazole, 1H-1,2,3- against HepG2, Huh-7 and A875 cell lines, respectively.
triazole-tethered isatin hybrids with potent antiproliferative ac- Sharma and co-workers tested the novel isatin-tetrazole hybrids
tivities [67]. (55, Fig. 45) for their anticancer activity against five human cancer
Eldehna and co-workers reported the synthesis and in vitro cell lines [71]. Compounds 55a and 55b exhibited potent anticancer
testing of novel isatin-pyridine hybrids (51 and 52, Fig. 42) against activity against DU-145 cell line with IC50 values in the range of
three human cancer cell lines including MCF-7 breast cancer, 4.26e7.01 mM, while the remaining compounds displayed moder-
HepG2 hepato-cellular carcinoma and A549 lung cancer [68]. ate to less cytotoxicity on human normal prostate epithelial
Compound 51 emerged as the most potent hybrid against the (RWPE-1) cells. Compound 55b effectively inhibited colony for-
HepG2 cell line (IC50 ¼ 2.5 mM) with 2.7-fold improved efficacy than mation of DU-145 cells and detained the cells in the G2/M phase of
doxorubicin, the reference drug (IC50 ¼ 6.9 mM). Compound 52a, on the cell cycle. Further studies such as AO/EB staining, DAPI nuclear
the other hand, was found to be the most active hybrid against staining, Annexin V binding assay, DNA fragmentation analysis,
A549 and MCF-7 cell lines with IC50 values of 10.8 and 6.3 mM, demonstrated that the scaffold 55b acts via induction of apoptosis
respectively. The incorporation of isatin and fluorine groups in the in DU-145 cell lines. This compound also resulted in collapse of
hybrids was found to be important in increasing their anticancer mitochondrial membrane potential along with raised intracellular
activity. ROS levels in DU-145 cells which confirmed that it has a potential to
Arpit et al. prepared new isatin-hydrazone hybrids (53, Fig. 43) provide lead for the treatment of prostate cancer.
and evaluated their cytotoxicity against the human cancer cells

N
N N
O N N
X N N
Cl
HN O
O
Isatin N
O Pyridine H N
51 52 H 52a
X = H, F, Cl, Br
Fig. 42. Isatin-pyridine hybrids (51 and 52) with the potent antiproliferative hybrid 52a.

Fig. 43. Isatin-hydrazone hybrids (53) with the potent compound 53a.
202 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Fig. 44. Isatin-dehydroepiandrosterone hybrids (54) with the potent compound 54a.

Fig. 45. Isatin-tetrazole hybrids (55) with the potent compounds 55a-b.

The molecular hybrids of isatin-triazole motifs (56, Fig. 46) highest potency against MGC-803 (IC50 ¼ 9.78 mM) by inducing cell
prepared by Yu et al. [72] exhibited selective inhibition against the cycle arrest at the G2/M phase, cellular ROS generation and was
MGC-803 (gastric) cell line in comparison to other cancer cell lines least toxic to normal cell lines HL-7702 (IC50 ¼ 40.27 mM) and GES-1
(TE-1 (human squamous cell carcinoma), MCF-7 (breast), and (IC50 ¼ 35.97 mM).
SW780 (urinary)). Compound 56a of the series displayed the A series of podophyllotoxin-isatin hybrids (57, Fig. 47) was
synthesized and screened for their cytotoxicity against adriamycin-
resistant K562/ADR cells and human leukemia K562 cells using the
CCK-8 assay [73]. All the synthesized hybrids showed higher anti-
proliferative potency against both cell lines than the control
Cl drugs viz. etoposide and adriamycin. SAR studies revealed that
Cl O O substitution at C-4 and C-6 positions of the isatin ring was suitable
Isatin for anticancer activities while substitutions at C-5 and C-7 positions
O O results in reduction of anticancer activity. Bromo-substitution at 4-
N N position or chloro-substitution at 6-position have shown to in-
crease anticancer potency. Among the synthesized hybrids, the
Cl Cl
cytotoxicity of the hybrid 57a was worth mentioning against
Triazole
N N N resistant K562/ADR cells with an IC50 value of 67 nM. Furthermore,
N N cell cycle analysis suggested that 57a remarkably induced K562/
N
R O ADR cell cycle arrest in the G2/M phase.
O O
56 A series of steroidal hybrids (58, Fig. 48) with different terminal
56a bioactives was synthesized using molecular hybridization approach
and screened for their anti-proliferative activity against a panel of
cancer cell lines of different origins using the MTT assay [74].
O HN HN Among the tested scaffolds, hybrid 58a (IC50 ¼ 4.06 mM) exhibited
N N potent inhibitory activity against SH-SY5Y (human neuroblastoma)
N
R= cells. It also arrested cell cycle at the G2/M phase via induction of
apoptosis accompanied with a decrease in mitochondrial mem-
O brane potential, thus inhibiting LSD1 (lysine-specific demethylase
Fig. 46. Isatin-triazole hybrids (56) with the potent compound 56a.
1) at low micromolar levels (IC50 ¼ 3.18 mM). Docking simulations
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 203

Isatin
O O
O O
O O Br
N N
O O
O R O
O O
O O
O O

O O O O Podophyllotoxin
O
57 57a O

R = H, 4-Cl, 4-Br, 5-CH3, 5-Cl, 5-Br, 6-Br, 5-F, 6-Cl, 7-F

Fig. 47. Podophyllotoxin-isatin hybrids (57) with the potent compound 57a.

Isatin Steroidal
O O
O O
Cl
O
O
N N N O
R N N N O
N
O N
58 Cl O
58a
R = H, 5-Cl, 5-Br, 5-F, 4-Cl, 4-Br, 4,7-diCl, 7-Cl

Fig. 48. Steroidal-isatin hybrids (58) with the potent antiproliferative hybrid 58a.

showed that the steroid motif played vital role in LSD1 inactivation. transduction might be the mechanism of action of these hybrids
[78].
2.11.1. Chalcone based hybrids Chen et al. synthesized chalcone-based hybrids (59, Fig. 49) via
Chalcones (1,3-diaryl-2- propen-1-ones) belong to the flavonoid aldol condensation of indamines' and indole carbaldehydes [79].
family and spectacle interesting biological activities. The tempta- Most of these hybrids displayed moderate to good anti-proliferative
tion of working with chalcones stems from their synthetic conve- activities in micromolar to submicromolar range. SAR studies sug-
nience, the diverse ways the core structure can be varied and their gested that the hybrids synthesized from 4,5,6-trimethoxy inda-
knack to confer drug-like activities to compound libraries appen- none with different indole carbaldehydes usually gave more potent
ded on them [75]. Chalcones received momentous attention for antiproliferative activities than the corresponding 5,6,7-trimethoxy
their anti-tumour properties, particularly in view of their identical indanone derivatives. Representative compound 59a, displayed
mode of action to the structurally related natural combretastatin impressive anticancer activity (GI50 ¼ 0.026e0.035 mM) against the
[76]. Chalcone is also deemed to be a promising template to A549 (lung), HeLa (cervical), Bel-7402 (liver carcinoma), PC-3
develop inhibitors of HIF-1 [77], a major mechanism for the survival (prostate) and K562 (gastric) cell lines. Mechanistic studies estab-
and evasion of tumour cells. A large number of literary reports have lished that 59a effectively inhibited in vitro cellular tubulin poly-
emerged on hybridization of chalcone with diverse heterocylic merization and caused cell cycle arrest in G2/M cell cycle.
moieties possessing promising anti-tumour activities. Disruption of In another study, a series of chalcone-b-carboline hybrids (60,
the cell cycle, induction of apoptosis, interference with p53-MDM2 Fig. 50) displayed potent activity (IC50 < 10 mM) and selectivity
interaction, antiangiogenesis, NF-kB pathway and cell signal against A-549 cell line after testing among a panel of cancer cell

R1 R9 Chalcone
N OCH3 H
R2 N
H3CO

R3
H3CO
R4 O
O 59a Indole
59
R1 = R2 = R3 = R4 = H, OCH3
R9 = H, CH3

Fig. 49. Chalcone-indole hybrids (59) with the potent compound 59a.
204 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

Fig. 50. Chalcone- b-Carboline based hybrids (60) with the potent compound 60a.

lines [80]. SAR, based on the cytotoxicity and DNA-binding studies, fluorinated chalcone exhibited the highest cytotoxicity with good
revealed the presence of fluoro and methoxy substituents at C-1 selectively against SW-620 and SKN-SH cell lines with IC50 values of
position of b-carboline for improved cytotoxicity as well as DNA- 0.35 and 0.39 mM, respectively.
binding potential whereas nitro, amino, trimethoxy and hydroxyl
substituents on the chalcone ring were encouraging for imparting 2.12. Imidazole based hybrid
significant cytotoxicity activities. Compound 60a, a prototype of the
series, showed superior activity (IC50 ¼ 5.30 mM) than harmine Four imidazole-based hybrids (63a-c and 64a) viz. imidazo-
against A-549 cell line. Further, docking studies have shown thiadiazole and imidazo-thiazoles (63e64, Fig. 53) prepared by
binding of these hybrids to DNA base pairs via H-bonding while b- Romagnoli et al. had IC50s in the range of 0.17e0.67, 0.042e0.61,
carboline moiety is essential for DNA intercalation. 0.25e0.87 and 0.20e0.86 mM against the L1210 (leukemia), FM3A
Zhang and co-workers also assessed the anticancer potential of (murine mammary carcinoma), CEM (human T-lymphocyte) and
chalcones coupled to benzoxaborole (61, Fig. 51) against human HeLa (cervix) cancer cell lines respectively [83]. These compounds
breast (MDA-MB231), ovary (SKOV-3) and colon (HCT-116) cancer at IC50 < 1 mM were highly cytotoxic to leukemia (HL-60 and U937),
lines [81]. They found that hybrid 61a (IC50 < 4.2 mM) had a higher melanoma (SKMEL-1) and the human leukemia U937 cell line over-
potency than cisplatin against SKOV-3 as well as low toxicity expressing Bcl-2 (U937/Bcl-2). Anticancer data revealed that ac-
(IC50 > 100 mM) to normal lung fibroblasts (WI-38). SAR studies tivity and selectivity was affected by the nature of substituents and
revealed that the introduction of hydrogen bond donors (-OH, their relative position on the phenyl ring tethered on imidazo[2,1-
-NH2) and electron withdrawing groups (-CF3, -NO2, -COOH) b] [1,3,4]thiadiazole and imidazo [2,1-b] [1,3]thiazole systems with
negatively influenced the anticancer activity. In contrast, the a preference for halogen (chlorine) substituent over methoxy.
replacement of iodine at the para-position increased selectivity 25- Further bio-isosteric replacement of phenyl with a thien-2-yl ring
folds toward SKOV-3 by decreasing toxicity to WI-38. improved efficacy. Cell death was found to be associated with the
Epipodophyllotoxin-chalcone scaffolds (62, Fig. 52) were syn- release of cytochrome c and activation of caspases.
thesized by Banday et al. and tested for anticancer activity against
six cancer cell lines [82]. Most of synthesized compounds have 2.13. Selenium/sulfur based hybrids
shown improved in vitro cytotoxicity than etoposide. Enhanced
potency may be either due to better target binding or increased Yan et al. reported the synthesis and anticancer activity of
solubility leading to better bioavailability. Compound 62a with a benzoselenazole-stilbene hybrids (65, Fig. 54) prepared by

Fig. 51. Chalcone-oxaborole hybrids (61) with the potent compound 61a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 205

O Epipodophyllotoxin O
N R'' N
N N
N N
O O
O O
O
O O
O O F

H3CO OCH3 H3CO OCH3


OR Chalcone
62 62a OH

O O O O O
R = H, CH3

R'' =

OCH3
O O O O

F F
O
F

OCH3

Fig. 52. Epipodophyllotoxin-chalcone based hybrids (62) with the potent compound 62a.

Br Imidazole Br Br
O Thiadiazole O O
NH NH NH
N N N N N N
R F
S N S S N S N
63 63a 63b

R = C6H5, C6H5CH2, C6H5(CH2)2, Thien-2-yl, p-F-C6H4, p-Cl-C6H4, p-Cl-C6H4CH2, p-CH3-C6H4, p-C2H5-C6H4, p-OCH3-
C6H4, p-OCH3-C6H4CH2, m-OCH3-C6H4, m-OCH3-C6H4CH2, m,p-(OCH3)2-C6H3, p-OC2H5-C6H4

O
Br Br Br
O O O
NH R NH NH
N N N
O N
S N S N S N
O 63c 64 64a
R = C6H5, p-Cl-C6H4, p-OCH3-C6H4

Compound IC50 (μM)


no. L1210 FM3A CEM HeLa
63a 0.17 0.37 0.41 0.67
63b 0.042 0.11 0.38 0.61
63c 0.25 0.61 0.83 0.87
64a 0.20 0.62 0.50 0.86
Fig. 53. Imidazo-thiadiazole hybrids (63 and 64) with the four potent anticancer compounds 63a-c and 64a.
206 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

R1 Benzoselenazole
O O
R1' R2 O
N O
Se R3 N
R2'
Se
65
R1 = H, OCH3; R2 = H, OCH3; R3 = H, OCH3 65a Stilbene
R1' = H, OCH3, Cl; R2' = H, OCH3

Fig. 54. Benzoselenazole-stilbene hybrids (65) with the potent anticancer hybrid 65a.

combining the pharmacophores resveratrol and ebselen [84]. 2.14. Nitric oxide (NO) releasing hybrids
Compound 65a with IC50 values of 1.01, 1.53, 1.52 and 3.37 mM
against the Bel-7402 (liver carcinoma), A549 (lung), HeLa (epithe- Huang et al. synthesized a series of nitric oxide (NO) releasing
lial cervical) and MCF-7 (breast) respectively, displayed promising furoxan-pyrazo annulated steroidal hybrids (67, Fig. 56) and eval-
anti-proliferative activities and established good TrxR inhibitory uated their in vitro anti-proliferative activity against five cancer cell
activities. The presence of methoxy substituents on the ring A of lines [86]. Amongst them, 67b displayed enhanced activity with
stilbene was crucial for anticancer activity with activity further IC50 values of 1.4, 3.4, 3.5 and 20 nM against four cell lines viz. MDA-
increasing with the introduction of 3,4-dimethoxy substituents. MB-231, SKOV-3, HUVEC and DU145. It also showed activity against
However, introduction of methoxy group on ring C reversed the a tamoxifen resistant breast cancer cell line (HCC 1806)
activity effects. It is interesting to observe that fluoro and chloro (IC50 ¼ 1.03 mM). SAR of the synthesized hybrids suggested that the
group on the ring C increased the anti-proliferative potency. linker at C-3 position of steroidal scaffolds with furoxan group was
Mechanistically, 65a exhibited cell apoptosis via G2/M cell cycle crucial for anti-tumour activity. Further, smaller substituents such
arrest in the human liver carcinoma Bel-7402 cell line. as hydrogen, methyl at 20th position of hybrid 67 were found to be
Mudududdla and co-workers prepared a series of thiophene- favourable for anti-proliferative activity. Furthermore, 67a and 67b
based hybrids (66, Fig. 55) and examined their in vitro VEGFR displayed better activity than 2-methoxystradiol (2-ME) in
(vascular endothelial growth factor receptors) and P-gp (P-glyco- reducing levels of VEGFR secreted by a MDA-MB-23 cell line. Both
protein) inhibition activity [85]. Compounds 66a and 66b displayed compounds suppressed the tubule formation.
VEGFR1 inhibition with IC50 values of 2.5 and 1.9 mM respectively, in Vannini and co-workers reported the synthesis of NOSH-aspirin
the cell-free enzyme assay. These two hybrids significantly inhibi- hybrids (68e70, Fig. 57) with ability to release hydrogen sulfide
ted VEGF-induced HUVEC (human umbilical vein endothelial cells) (H2S) and nitric oxide (NO) [87]. These compounds inhibited the
migration and decreased the number of migrated cell percentage growth of two human colon cancer cells (HT-29 and HCT-15) by
from 100 to 20%. Both compounds (66a and 66b) not only showed generating reactive oxygen species leading to cancer cell regres-
inhibition of P-gp efflux pumps but also synergized the anticancer sion. The growth inhibitory effect of 68a, 69a and 70a was associ-
activity of doxorubicin in human colorectal carcinoma LS180 cells. ated with G1 to S cell cycle arrest along with inhibition of
Compound 66a showed fourteen folds enhanced IC50 of doxoru- proliferation and induction of apoptosis. These ortho (68a), meta
bicin in LS180 cells. (69a) and para (70a) NOSH-aspirin hybrids displayed IC50 values of

Fig. 55. Thiophene-benzdioxole hybrids (66) with the potent hybrids 66a-b.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 207

Fig. 56. Nitric oxide (NO) releasing-furoxan hybrids (67) with the active antiproliferative compounds 67a and 67b.

S
S
S O O
S O S
O S
R O S
O S S
R
R1 R2
O O
O ONO2
ONO2 ONO2
O O
O
68 69 70
R1 = R2
=H R = H, OMe, Cl
R = H, OMe, Cl R1 = OMe, R2 = H
R1 = H, R2 = Cl

S
S
Aspirin S O O
S O S
O S
O S
S S
O NOSH
68a 69a O
O O ONO2
ONO2
ONO2 O 70a
O O

Compound IC50 (μM)


no. HT-29 (Colon) HCT 15 (Colon)
68a 48 57
69a 220 110
70a 450 380
Fig. 57. Nitric oxide (NO) releasing-NOSH-aspirin hybrids (68e70) with the potent compounds 68a, 69a and 70a.

48, 220 and 450 nM, respectively against HT-29 (colon) cancer cell observed against the HCT-15 (colon) cell line. o-NOSH-aspirin was
line; while the respective IC50 values of 57, 110 and 380 nM were the most potent amongst the positional isomers followed by m-
208 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

O
H O- O
O H O-
O O N+ R1
O O n N N O O O N+
O O 3 N N
OH O O R2
H OH O O O
OH H
71 OH 71a
n = 2, 3
N
R1R2N = NH
O

Fig. 58. Nitric oxide (NO)-releasing oridonin hybrids (71) with the potent antiproliferative hybrid 71a.

NOSH-aspirin (69a) and p-NOSH-aspirin (70a). line. In addition, 73b strongly inhibited the growth of Hep-G2, A549
A number of nitric oxide (NO) releasing oridonin-diketoester and MCF-7 cells lines. A combination of fluorescent staining ex-
hybrids (71, Fig. 58) were synthesized and evaluated for their amination and flow cytometric analysis confirmed that 73a
anti-proliferative activity by Xu et al. [88]. Most compounds
exhibited anti-proliferative activity in human leukemia Bel-
7402 cells with IC50 values ranging from 1.84 to 17.01 mM.
Conspicuously, the most active compound 71a displayed good
inhibitory activity (IC50 ¼ 1.84 mM) against the Bel-7402 cancer cell H H
line. Nitric oxide (NO) release assay revealed that synthesized O O
compounds have potent anti-proliferative activities due to high n
O O
levels of NO production from diazeniumdiolates, and the synergic
effects of oridonin and NO donor moiety. Moreover, preliminary HO 73 OH
mechanistic studies found that the most potent compound, 71a
n = 2, 4, 6, 8
induced apoptosis and arrested cell cycle at the S phase in Bel-
7402 cells.

H H
2.15. Natural product based hybrids
O O
6
Oleanolic acid coupled 1H-1,2,3-triazole hybrids (72, Fig. 59) O O
displayed potent anticancer activity relative to 5-FU against five
human cancer cell lines [89]. Generally, hybrids bearing para sub- HO 73a OH
stituents (preferably electron withdrawing) on the aromatic ring
Oleanolic acid
were observed to be more potent in comparison to those bearing
ortho or meta substituents. Compound 72a displayed excellent
inhibitory activity (IC50 ¼ 3.51 mM) against HT1080 cancer cells and
was shown to be a potent apoptosis inducer. H
H H H
Five dimeric oleanolic acid tagged diamines (73, Fig. 60) were N N
synthesized and tested for their antitumor potential against five 6
human cancer cell lines using MTT assay [90]. Cytotoxicity data O O
suggested that anti-proliferative potency did not depend on the
AcO 73b OAc
length of alkyl chain between two carboxyl groups of the dimer.
The hybrids, 73a (IC50 ¼ 0.51 mM) and 73b (IC50 ¼ 0.1 mM) showed
superior anti-proliferative profiles than 5-FU against the A549 cell Fig. 60. Dimeric oleanolic acid hybrids (73) with the potent antitumor hybrids 73a-b.

Triazole

R N N
N N N
N O NO2
O
O
O
HO Oleanolic acid
HO
72 72a

R = o--Me, m-OMe, p-OMe, o-Me, p-Me, p-OEt, o-F, m-F, p-F, m-Cl, p-Cl, o-Br, m-Br, p-Br, o-Ac,
m-Ac, p-Ac, o-NO2, m-NO2, p-NO2, o-CN, m-CN, p-CN, m-COOMe, H

Fig. 59. Oleanolic acid based hybrids (72) with the potent compound 72a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 209

induced Hep-G2 cell apoptosis by cell cycle arrest at the G1 phase. 2.15.1. Drug modified anticancer hybrids
Cai and co-workers designed and synthesized diaryl-1,2,4- Molecular hybrids (76 and 77, Fig. 62) of different non-steroidal
triazole-caffeic acid (CA) hybrids (74 and 75, Fig. 61) as anti-inflammatory (NSAIDs) drugs with tyrosine kinase inhibitor of
cyclooxygenase-2 (COX-2)/5-LOX dual inhibitors for cancer treat- epidermal growth factor receptor (EGFR), Erlotinib were synthe-
ment [91]. Anti-proliferative activity data revealed that compounds sized and evaluated for their anti-proliferative and pharmacoki-
with electron withdrawing group proved to be favourable for netic activity against HCC827 (lung) and A431 (squamous
enhancement of COX-2 inhibitory activity while compounds having carcinoma) tumour cell lines [92]. Anti-proliferative data indicated
hydroxyl group was found to be critical for 5-LOX activity. Com- the synthesized compounds possess comparable activity to the
pounds 74a (COX-2, IC50 ¼ 0.29 mM) and 75a (IC50 ¼ 6.78e9.05 mM) positive control, erlotinib. Among the synthesized hybrids, 76a and
exhibited excellent COX-1/COX-2 selectivity against A549 (lung), 77a exhibited excellent potency with both compounds exhibiting
Caco-2 (colon), PC-3 (prostate) and B16-F10 (murine-melanoma). IC50 values of 0.3 mM against HCC827 (lung) cancer cell line.
Mechanistic studies revealed that 74a blocked the cell cycle in the
G2 phase and induced apoptosis in A549 cells in a dose dependent
manner. 3. Conclusion

The concept of anticancer hybridization is ever evolving and

R1
F Caffeic acid
Triazole

O R3
N N O OH
N N
S nO OH
N O S 3O OH
R2 N
74 R1 = H, Br, F H3C S
R2 = CH3SO2, NH2SO2 O
74a
R3 = OH, OCH3, OAc
n = 2,3
R1 F3C

O R3 O OH
N N N N
O OCH3 O O OCH3
S 2 N S 2
N
R2 R1 H3C S
75
= H, CH3 75a
O
R2 = CH3SO2
R3 = OH, OCH3, OAc

Fig. 61. Caffeic acid-triazole hybrids (74 and 75) with the potent antitumor hybrids 74a, 75a.

HN O HN
O R O
O N O N
R O O
O N O N
O 77
76 R = Aspirin, Ibuprofen, sulindac, Naproxen,
R = Aspirin, Ibuprofen, sulindac, Naproxen, Indomethcin, Ketoprofen
Indomethcin, Tamibarotene

Erlotinib
HN
O HN
O
O N O
O N
O
O N O H3C O
O N
O O O 76a
77a

Fig. 62. Erlotinib-NSAID hybrids (76 and 77) with the potent compounds 76a and 77a.
210 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212

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