international journal for pharmaceutical research scholars ...2 angiogenesis, the formation of new...

International Journal for Pharmaceutical

Research Scholars (IJPRS)

V-7, I-1, 2018 ISSN: 2277 - 7873

REVIEW ARTICLE

© Copyright reserved by IJPRS 82

Benzimidazoles as Anti-VEGFRs: A Review

Ankita Pathak*1, Romana Zulfiqar2, Sanjar Alam3 1Doctor of Philosophy, Jamia Hamdard University, Hamdard Nagar, New Delhi, India.

2General Manager, APCER Life Science 3Associate Professor, KIET School of Pharmacy, UPTU

Manuscript No: IJPRS/V7/I1/00013, Received On: 23/02/2018, Accepted On: 28/02/2018

ABSTRACT

Angiogenesis can be regarded as a hallmark to deal with different type of cancers as they help tumors

proliferate and metastasize. A major angiogenic inducer released by many tumors, vascular endothelial

growth factor (VEGF) predominantly dimerizes with the VEGFR2 receptor. The same can be used both

as a surrogate biomarker for biological drug activity and a promising target for inhibitors. But, inhibitors

are quickly hijacked by tumor cells in more invasive and aggressive forms resulting in resistance and

hence poor drug delivery towards tumors. Understanding the current problem there is an urge to design a

multi-targeted molecule with appropriate pharmacophoric features to enhance potency along with

reduced toxicity and resistance. The present review focuses on synthesis, characterization and biological

activity of novel benzimidazole derivatives based on generated Pharmacophore model. These drugs will

serve our purpose of discovering novel anticancer agents against the VEGFR that are overexpressed and

their capability to decrease the resistance.

KEYWORDS

Benzimidazole, VEGFR, VEGF, Angiogenesis, HIF, Anti-VEGFRs

INTRODUCTION 1

Angiogenesis, the formation of new blood 2 vessels from pre-existing microvasculature, is a 3 complicated process that usually occurs during 4

wound healing, organ regeneration, and the 5 female reproductive cycle1. It can also happen 6 in cancer, whereby the newly created capillaries 7 supply growing tumors with nutrients and allow 8

waste removal2,3. Primary tumors, as well as 9 metastatic foci, require oxygen and nutrient 10 transport necessitating sustained angiogenesis. 11 Capillaries must be within a distance of 1-2mm 12 to ensure that cells receive appropriate oxygen 13

and nutrients.4 14

15

16

17

18

19

In malignant angiogenesis, continuous 20 stimulation by the tumor and stromal cells is 21 required to support new growth5 22

If new vessel growth cannot keep up with the 23 rapid growth rate of the tumor, hypoxia ensues, 24 and the tumor can become necrotic. This 25 condition of oxygen deprivation is an essential 26

trigger for tumor vessel growth. There are more 27 than dozen endogenous proteins that can act as 28 positive regulators or activators of tumor 29 angiogenesis. A hypoxic environment stabilizes 30 hypoxia-inducible factor-1(HIF-1 6 HIF-1 is the 31

primary transcriptional regulator of VEGF. 32

HIF-1 also regulates other target genes: pro-33 angiogenic cytokines such as fibroblast growth 34 factor-3 (FGF-3) and hepatocyte growth factor 35 (HGF), transcription factors such as annexin V, 36

insulin-like growth factor binding proteins 1,2 37

*Address for Correspondence: Ankita Pathak, Doctor of Philosophy, Jamia Hamdard University, Hamdard Nagar, New Delhi, India. E mail ID: [email protected]

mailto:[email protected]



and 3 and heat shock factor, and various 1

integrins and matrix metalloproteinases.7 2 Angiogenesis can be promoted both by pro-3 angiogenic cytokines such as VEGF secreted 4

from neoplastic and inflammatory cells as well 5 as upregulation of pro-angiogenic receptors 6 such as VEGFR. Additional important 7 regulators of angiogenesis include tumor 8 necrosis factor α (TNF-α), basic fibroblast 9

growth factor (bFGF), angiopoietin-1 and 10 angiopoietin-2, interleukin-8 (IL-8), and 11

platelet-derived growth factor β (PDGF-β)6,8,9. 12 Pro-angiogenic factors are balanced by the 13 significant anti-angiogenic/inhibitory factors 14 including angiostatin, endostatin, interferon-α, 15 and interferon-β10 Candidate ABT-869, 2, is 16

currently in phase II trials as VEGFR 17

inhibitors13. 18

Vascular endothelial growth factor (VEGF) is a 19 critical pro-angiogenic cytokine released by 20

many tumors, and the angiogenic activity of the 21 VEGF family of proteins is mediated by three 22

VEGFR receptors (VEGFR-1, VEGFR-2, and 23 VEGFR-3). The VEGFR- 2 receptors, the 24

principal kinase involved in multiple processes 25 of angiogenesis has, therefore, became an 26

attractive cancer target for which many small 27 molecules have been developed. Compound 28 BMS-540215, 1, which emerged from potent 29

indole-based VEGFR-2 kinase inhibitors have 30 shown excellent enzymatic potency against 31

VEGFR-2, a good kinase selectivity profile, an 32

acceptable safety profile, and robust preclinical 33 in vivo activity against a variety of human 34 tumor xenograft models11,12. 35

36

37

1 38

39

40

41

42

2 43

44

For new vessels to develop, vasodilatation and 45

increased vascular permeability must occur. 46 Endothelial cells become activated and migrate 47 through the basement membrane. The milieu of 48

activated cytokines promotes signaling and 49 survival of these endothelial cells. The cells 50 invade the extracellular matrix (ECM) and 51 begin to form tubular structures. Subsequent re-52 organization of the ECM helps to support the 53

newly formed tubular structures9. The single 54 most important factor in angiogenesis is 55

vascular endothelial growth factor (VEGF-56 A/VEGF). VEGF, a selective mitogen for 57 endothelial cells, increases microvascular 58 permeability and leakage. Although necessary 59 for healthy development and wound healing, 60

VEGF over-expression has been demonstrated 61

in tumors across species and is associated with 62 malignant angiogenesis. VEGF also increases 63 malignant cell trans-endothelial migration in 64

vitro7. Serum VEGF levels are elevated in dogs 65 with osteosarcoma and pretreatment elevation is 66

correlated with a disease-free interval. In 67 people, over-expression of VEGF is linked to 68

disease progression and poor prognosis in 69 various carcinomas as well as osteosarcoma. 70

Thus, VEGF may be useful both a surrogate 71 biomarker of drug biologic activity as well as a 72 target for therapy. Another potential surrogate 73

biomarker of anti-angiogenic therapy is tumor 74 hypoxia. Direct tumor hypoxia can be measured 75

by the use of a probe to measure oxygen 76 concentration within the tumor, or in a 77

surrogate manner using endogenous markers 78 such as HIF-1 or exogenous probes 79

(pimonidazole and EF5). In human cancer 80 patients, tumor hypoxia may have prognostic 81 and predictive significance14. 82

Tumors may also promote angiogenesis by up-83 regulating VEGF receptors, specifically 84

VEGFR-1 (flt-1), VEGFR-2 (flk-1/KDR), and 85 less importantly heparin sulfate proteoglycans, 86 and neuropilins15. The VEGF receptors are 87

structurally similar, having an extracellular 88 ligand-binding region comprised of seven 89 immunoglobulin-like loop domains attached 90 with a short trans-membrane helix to a 91

cytoplasmic catalytic domain. VEGFR-1 is 92 expressed on both endothelial cells and 93



monocytes while VEGFR-2 is limited to the 1

endothelium [17]. VEGF is secreted by nearly all 2 solid tumors in response to hypoxia. 3 Upregulation of VEGF has been clearly 4

demonstrated in human cancers16,18. 5

VEGFR- Inhibitors 6

Many anti-angiogenic and anti-vasculogenic 7 drugs exist. Some inhibit endothelial cells 8 directly while others inhibit the signaling 9

cascade or impair the ability of endothelial cells 10 to break down the ECM. 11

The specific targeting of VEGF involves 12 prevention of ligand-receptor interaction 13 through ligand sequestration with a VEGF 14 antibody, competitive inhibition of kinase 15

activity or blocking the binding of VEGF-A 16 with a monoclonal antibody to the receptor [19]. 17

One of the few FDA approved and best known 18 VEGF inhibitors used in human medicine is 19 bevacizumab (Avastin). Bevacizumab is a 20

humanized monoclonal antibody that targets 21

VEGF-A in the treatment of various cancers, 22 including colorectal, lung, breast, kidney, and 23 glioblastoma.17,20 Antibody therapy in 24

veterinary medicine lacks due to the cost of 25 development and functionality. However 26

tyrosine kinase inhibitors (TKIs) have gained 27 significant popularity over the last decade. TKIs 28 work by blocking (reversibly or irreversibly) 29

the ATP binding site of a kinase. If ATP cannot 30 bind, the kinase cannot phosphorylate itself or 31

initiate downstream signaling20. VEGF, 32 PDGRF, and FGFR are members of the 33 receptor tyrosine kinase family, and their 34 blockade prevents both auto-phosphorylation 35

and signal transduction thereby stopping the 36 angiogenic signal. The advantage of a TKI is 37 twofold in that it is effective against cancers 38 that have upregulation of VEGF and/or VEGF 39 receptors. The TKIs as small molecule 40

inhibitors have been very successful as anti-41 cancer therapies both alone and in combination 42

with tradition cytotoxic therapies. Some BZs 43 also exhibit tyrosine kinase inhibition, and this 44 may be another mechanism of therapeutic 45 activity in addition to MTI. ABZ appears to 46

47

inhibit VEGF in malignant ascites 48

formation21,22, and more recently, a series of 49 novel BZ derivatives have been shown to 50 inhibit various growth factor receptors (EGFR, 51

VEGFR-2, and PDGFR).[23] The molecular 52 mechanism of these actions has not been well 53 described. Further investigation into optimal 54 anti-cancer BZ drug/dose as well as elucidation 55 of the mechanism by which they inhibit tumor 56

growth may open the door to novel adjunctive 57 therapy. 58

Benzimidazoles 59

Benzimidazole, because of their diverse 60 biological activity and clinical applications this 61 ring system was proved to be very important as 62

it is involved in numerous antiparasitic, 63 antitumor and antiviral drugs. It is also well 64

known that these molecules are present in a 65 variety of antioxidant and anti-allergic agents. 66 Many derivatives of benzimidazole show 67

antiparasitic and antiprotozoal activities. In 68

recent years, benzimidazole derivatives have 69 attracted particular interest due to their 70 anticancer activity. Benzimidazole showed 71

anticancer activity against DNA Topoisomerase 72 I and colon cancer cell lines. The need for 73

anticancer agents that selectively kill or inhibit 74 the growth of neoplastic cells without affecting 75 non- cancerous host tissues is high and 76

persistent. 77

There are two general methods for the synthesis 78

of 2-substituted benzimidazole. 79

Synthetic Pathways 80

One is a coupling of o-phenylenediamines and 81 carboxylic acids24 or their derivatives (nitriles, 82

imitates, or orthoesters)25, which often require 83 strong acidic conditions, and sometimes 84 combined with very high temperature or the use 85 of microwave irradiation26. 86

The other way involves a two-step procedure 87

that is oxidative cyclodehydrogenation of 88

aniline Schiff's bases, which are often generated 89

in situ from the condensation of o-90 phenylenediamines and aldehydes. 91

92

93



Other Methods : Synthetic Approach 1

Benzimidazoles are generally prepared by the 2 condensation of o-phenylenediamine with 3

organic acids employing hydrochloric acid,28 4 polyphosphoric acid,29 boric acid30 or p-toluene 5

sulphonic acid31 as a catalyst. In addition, the 6 title compounds also can be obtained either by 7 reduction of o-nitroaniline derivatives or by 8 reaction of organic acids derivatives with o-9 phenylenediamine32. Yet these reactions are 10

often carried out under high pressure and 11 require for long reaction times. Therefore, the 12 discovery of mild and practical routes for the 13 synthesis of benzimidazoles continues to attract 14 the attention of researchers. 15

Several improved procedures for the 16 preparation of benzimidazoles have been 17

reported, either by fusion of 2-aminobenzamide 18 and organic acid,33 or by reaction of o-19 phenylenediamine and organic acid using 20 FeCl3/O2 as a catalytic Fe3O/Fe2O redox 21

cycling approach34. Recently, Villemin et al.35 22

and Loupy et al.36 reported a fast and 23 convenient synthesis of benzimidazoles by 24

condensation of orthoesters with o-25 phenylenediamine in dry medium and using 26 KSF clay under mono-mode microwave 27

irradiation. Guillermo Penieres et al.37 also 28 obtained 2-alkyl benzimidazoles using natural 29 clay under infrared radiation in solvent-free 30 conditions. In addition, the development of 31

novel, but more complicated solid phase routes 32 to benzimidazoles had been advanced38. 33 Microwave irradiation of organic reactions has 34 rapidly gained in popularity as it accelerates a 35 variety of synthetic transformations39. The 36

application of microwave irradiation with the 37

use of catalysts or mineral supported reagents, 38

under solvent-free conditions, provides unique 39 chemical processes with special attributes such 40 as enhanced reaction rates, higher yields, 41 greater selectivity and ease of manipulation. 42

Therefore, microwave irradiation in organic 43

R

NH2

ROHC

N

HN

R'

R

R=H, CH3, Br, NO2 R= H, CH2, Cl...

Cat/ H2O2

EtOH, R. T.

Cat = Fe3O4 / SiO2(NH4)MO2O212 examplesup to 95.2% isolated yield

NH

The identity of the ortho-substituent of an aryl azide influences its reactivity toward transition

metals. Substitution of a vinyl group with an imine disables rhodium (II)-mediated Hamination

triggers a Lewis acid mechanism catalyzed by iron(II) bromide to facilitate benzimidazole

formation27.



synthesis has been the focus of considerable 1

attention in recent years and is becoming an 2 increasingly popular technology40. Reactions in 3 ‘‘dry media’’ or under solvent-free conditions 4

are especially appealing as they provide an 5 opportunity to work with open vessels, thus 6 avoiding the risk of high-pressure development 7 and with the possibility of upscaling the 8 reactions to more significant scale. Solventless 9

procedures without the use of supporting 10 reagents are particularly eco-friendly41. 11

12 H2O2/HCl solvent system was examined here 13 for the synthesis of 2-substituted 14

benzimidazoles in acetonitrile at room 15 temperature. A ratio of 1:1:7:3.5 of 1,2-16

phenylenediamine/aryl aldehyde/H2O2/ HCl 17 was found to be optimum for the coupling of 18 aryl aldehydes and phenylenediamines. 19

Mechanism of Action, Toxicity, Metabolism, 20

and Efficacy 21

As an antiparasitic, a BZ (Benzimidazole) acts 22 by binding to the tubulin within the parasite 23

resulting inhibition of cell division and 24 polymerization of microtubules via disruption 25

of the mitotic spindle. In vitro, BZs prevent 26 polymerization of tubulin into microtubules via 27 suppression of the mitotic spindle and 28

disruption of the microtubule-kinetochore 29

interaction. The loss of tension leads to poor 30 chromosomal alignment42. This causes the cells 31 to arrest in G2/M, and the cell cannot enter 32 mitosis. Cell death ensues via apoptosis. BZs 33 can also uncouple oxidative phosphorylation in 34

mitochondria. This disruption causes altered 35 metabolism and inhibition of cellular transport 36 in the cell.43,44 In a time-dependent manner, 37 energy reserves become depleted, and waste 38 excretion becomes inhibited leading to cell 39

death.45 Possible additional mechanisms of 40 action have been reported with other BZs. The 41

BZ carbendazim appears to target DNA 42 directly; it can induce oxidative stress and 43 epigenetic regulation through hypomethylation. 44 Global changes in methylation patterns are a 45

characteristic trait of many tumors. 46

Benzimidazole derivatives have also been used 47 as anti-cancer inhibitors of PGP (a drug efflux 48 pump important in chemo-resistance) and 49

topoisomerase I (an enzyme that relaxes DNA 50 supercoiling during replication and 51 transcription).46 It has also been proposed that 52 BZs can inhibit histone deacetylase resulting in 53 hyperacetylation of histones and subsequently 54

affect gene expression47. Mebendazole (MBZ) 55 has been shown to induce apoptosis through 56

inactivation of Bcl-2, a protein which 57 suppresses apoptosis by preventing the 58 activation of the caspase pathway. In addition, 59 some BZ derivatives have demonstrated 60 inhibition of EGFR, VEGFR-2 and PDGFR 61

kinase activity, which are commonly 62

upregulated in many cancers46,48. Thus, 63 although microtubule inhibition resulting in cell 64 cycle arrest and apoptosis is likely to be the 65

primary anti-cancer mechanism of BZs, other 66 intracellular mechanisms may play a role. 67

Benzimidazoles as Anti-cancer Agents 68

In the early 1950s, the anti-cancer potential of 69

the BZs was first discovered when they were 70 added to other compounds such as nitrogen 71

mustard and showed inhibition of carcinoma, 72 mammary adenocarcinoma, and sarcoma in 73 mice.49 In the 1980s further, work with various 74

benzimidazole alkylating agents in combination 75 with nitrogen mustard derivatives and 76

benzothiazole alkylating agents showed 77

efficacy against lymphocytic leukemias50,51. 78 Over the next 30 years, BZs were more 79 thoroughly evaluated for their anticancer 80

effects. Multiple BZ analogs have been 81 evaluated in people and rodent tumor models. 82 The results are incredibly variable, dependent 83 not only on species and tumor type but also 84 dose rate and time. Early work with seven BZ 85

analogs revealed significant inhibition of 86 growth to normal lymphocytes via mitotic arrest 87 by MBZ, parabendazole, cambendazole, and 88

FBZ (Fenbendazole). Other analogs, 89 thiabendazole and oxfendazole (OFZ) showed 90 no activity52. Limited information regarding the 91 use of FBZ in both people and animals as a 92

specific anticancer therapy exists. It was noted 93



incidentally that FBZ routinely administered in 1

rat food inhibited tumor growth of human 2 xenograft lymphoma when combined with 3 dietary vitamin supplementation (vitamin B, D, 4

K, E, and A)31. 5

In vitro and In vivo Evidence of Anti-cancer 6 Effects 7

Many BZ derivatives have been evaluated in 8 vitro and in vivo over the last 20 years. A BZ 9

has previously been shown to have strong 10 antiproliferative in vivo and in vitro effects 11

against colorectal cancer and hepatocellular 12 carcinoma (HT-29) in people.14,53,54 MBZ 13 induces mitotic arrest in non-small cell lung 14 cancer in mice xenografts.55 In another study, 15

MBZ had antitumor effects on human lung 16 cancer cell lines in vitro and in vivo. 17

Flubendazole has demonstrated clinical activity 18 against leukemia and myeloma xenografts 19 especially in combination with vinca 20

alkaloids56. A larger study demonstrated 21

cytotoxic effects of carbendazim and benomyl 22 on immortalized human cell lines and primary 23 cell cultures from cancer patients, including 24

leukemia, myeloma, lymphoma, small cell lung 25 cancer, renal and cervical adenocarcinoma47. 26

Benomyl appears more potent than the 27 metabolite carbendazim (noted with many 28 drugs) and is more effective against 29

hematologic malignancies while the metabolite 30 carbendazim is more effective against solid 31

tumors47. Carbendazim also demonstrated 32

potent antitumor activity against murine B16 33 melanoma and human HT-29 colon carcinoma 34 cell lines57. 35

More recently, a new generation of synthesized 36 BZ-based agents has also shown anticancer 37 effects against murine melanoma models via 38 PARP-1 (Poly (ADP-ribose) polymerase-1), 39 which has a role in repair of single-stranded 40

DNA (ssDNA) breaks58. The addition of BZ 41 ligands to existing drugs such as cisplatin 42

analogs has in vitro anti-proliferative effects on 43 human MCF-7 breast and HeLa cervical cancer 44 cell lines59. Derived compounds, such as 2-45 substituted BZs also have anticancer effects. 46 Examples of this include bis-bezimidazole 47

derivatives that interfere with DNA 48

topoisomerase I and are cytotoxic against breast 49

adenocarcinoma and skin epidermoid 50 carcinoma. Another example is methyl-2-51 benzimidazole carbamate; this agent induces 52

apoptosis in cancer cells54. A novel derivative, 53 MPTB, can also induce apoptosis in human 54 chondrosarcoma cells60. Various derivatives of 55 2-mercapto benzimidazoles in one study 56 showed antiproliferative activity with notable 57

activity in G2/M phase arrest with time-58 dependent induction of apoptosis. Thiazolo-59

benzimidazole derivatives also activate 60 apoptosis61. Thus, many BZ drugs exhibit 61 anticancer properties, with demonstrated 62 efficacy against a broad spectrum of tumor 63 types and several potential mechanisms of 64

action. Other recent discoveries consisting of 65

anti-cancerous activity includes:- 66

Zienab M. Nofal et al., Compounds had a 67 promising anticancer activity against cell lines 68

PC12. Thus, with further testing, many of the 69 synthesized compounds especially compound 3 70

have the potential to be developed into potent 71 anticancer agents against HepG262. 72

73

Blaszczak-swiatkiewicz K., et al., synthesized 74 heterocyclic compounds; belong to a new group 75 of chemical bandings with potential anticancer 76

properties. These compounds belong to the 77 group of drugs with the bioreductive 78 mechanism of action Moreover, derivatives 79 containing benzimidazole ring 4 are active as 80 human DNA Topoisomerase I inhibitors63. 81

82



Mohammed Hadi Al–Douh et al., synthesized 1

some new benzimidazole derivatives, showed 2 high cytotoxic activity against MCF-7 cell lines 3 and moderate cytotoxic activity against HCT-4

116 cell lines. Both benzimidazoles 5 and 6 5 showed moderate cytotoxic activity against 6 MCF-7 cell lines, while the benzimidazole 7 7 showed no cytotoxic effect with both MCF-7 8 and HCT-116 cell lines. This preliminary study, 9

benzimidazoles 6 and 8 showed more promising 10 results compared to other benzimidazoles. 11

However, it is imperative to expand the study to 12 include other types of cancer cell lines as well 13 as normal cells in order to determine whether 14 these two benzimidazoles 6 and 7 are suitable 15 candidates for the development of new anti-16

cancer drugs64. 17

18

O. B. Patel, et al., The 2-(aryl)-1-(1H-benzo[d] 19 imidazole-1-yl) ethanone and 2-(aryl)-1 (2-20 methyl- 1Hbenzo[d]imidazol-1-yl) ethanone 21

compounds were synthesised. Compound 9 was 22 screened for cytotoxic activity by XTT based 23 cell viability assay method by using two human 24 cell line VERO and NCI65. 25

26

Sabiha Alper, et al., synthesized some new bi- 27

and tert-benzimidazole derivatives inhibitor of 28

Topoisomerase II. The compound 10 exhibit 29 potent antiproliferative activity against a range 30

of ovarian cell lines and to inhibit transcription 31 in an in vitro setting66. 32

33

Mostafa M. Ramla, et al., Different substituent 34 were introduced in position 1 of 2-methyl-5(6)-35

nitro-1H- benzimidazole in order to obtain 36 different side chains having different 37 heterocyclic compounds, for example, 38

thiadiazoles, tetrazoles, triazoles, thiazoles, 39

triazines, and imidazoles. The antitumor effect 40 of the compound 11 was studied against breast 41 cancer (MCF-7) and compound 11 [IC50 = 4.52 42

l g] was found to be active67. 43

44

Benzimidazole as a Possible Therapy for 45 Resistant Tumors 46

Acquired tumor resistance to chemotherapy 47 necessitates novel therapies for successful 48 cancer treatment. The drugs most often 49

associated with acquired resistance are 50 paclitaxel, docetaxel, vinca alkaloids, 51 doxorubicin, daunorubicin, epirubicin, 52 etoposide, dactinomycin, and mitomycin C68. 53

Many mechanisms of tumor resistance exist. A 54 frequently encountered mechanism involves 55 cells with the MDR (Multi-Drug Resistant) 56

phenotype that utilizes alterations in the Golgi 57 apparatus, lysosomes and other organelles that 58 affect post-translation pathways. The Golgi 59



apparatus is central to maintaining growth and 1

survival of cancer cells and may be an 2 additional therapeutic target site. A BZ based 3 chemical compound, 2-(substituted phenyl)-4

benzimidazole can displace the resident Golgi 5 proteins by inhibiting its ability to recycle these 6 proteins leading to inhibition of cell 7 proliferation69. Another resistance mechanism 8 involves PARP-1 (Poly (ADP-ribose) 9

polymerase-1). PARP-1 is activated by DNA 10 damage, causing it to cleave NAD+ and transfer 11

ADP-ribose units which aid DNA repair, 12 allowing cancer cells to evade apoptosis 13 following DNA damage. Some cancer cells 14 overexpress PARP-1, making it an attractive 15 target. Various formulation and chemical 16

alterations of BZ cores such the addition of a 17

piperidinyl or pyrrolidinyl +/- an alkyl group on 18 the nitrogen at the 2 position demonstrate 19 positive enzymatic and cellular assay results for 20

PARP-1 inhibition. Continued modifications 21 demonstrate improved pharmacokinetic 22

properties and potent oral efficacy, making BZs 23 yet more attractive as novel anticancer agents58. 24

CONCLUSION 25

Angiogenesis is necessary for continued 26

primary tumor growth as well as establishing 27 distant metastases. Regulation of angiogenesis 28 is primarily by a vascular endothelial growth 29

factor (VEGF). Given that sustained 30 angiogenesis is necessary for tumor growth, 31

therapeutic strategies which reduce or block the 32

effects of tumor-associated VEGF are currently 33 being investigated for the treatment of various 34 cancers and have improved survival in many 35

cancers and may help to delay progression of 36 micro-metastasis. 37

Since the original finding of elevated 38 VEGFS concentrations of in patients with 39 cancer , many studies have reported similar 40

findings in patients with breast cancer and 41 many other types of cancer, with higher levels 42

often found in metastatic disease than in 43 localized disease or in progressive disease 44 during treatment70 . Correlations with prognosis 45 have also been reported for several 46 cancers, e.g., ovarian cancer. 47

It has been testified that VEGF also plays an 48

important role in the growth of sinusoidal 49 endothelial cells and hepatocyte, or termed liver 50 regeneration and in the development of primary 51

and secondary liver carcinoma and benign liver 52 pathological changes such as hemangioma, 53 focal hyperplasia, and hepatitis, and hepatitis by 54 promoting neovascularization71. VEGF is 55 expressed mainly in HCC cells (Hepato 56

Carcinoma Cells), sinusoidal endothelial cells, 57 Kupffer cells, epatic macrophages etc. These 58

results demonstrate that VEGF signaling is both 59 important for SEC (sinusoidal endothelial cells) 60 development and required for lipoprotein 61 uptake in the liver. The study provides evidence 62 for VEGFR2 role in liver metastasis and hence 63

can be used as a target to study against liver 64

cancer72. 65

Various clinical trials have validated the clinical 66 importance of anti-VEGF or anti-VEGF 67

receptor (VEGFR) therapy. Currently, the 68 humanized monoclonal antibody bevacizumab 69

(blocks VEGF-A), and the tyrosine kinase 70 inhibitors sunitinib and sorafenib (inhibit 71

VEGFRs) are approved for patients with 72 various malignancies and several others are 73

expected in the coming years. Unfortunately, 74 anti-VEGF/VEGFR treatment is not void of 75 side effects. An array of unexpected side effects 76

is now seen in clinical practice73. 77

It is, therefore, worthwhile to synthesize 78

oxindole bearing benzimidazole moiety which 79

may have less toxicity and more potentiality for 80 VEGFR. 81

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