Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Novel Synthetic Indazoles Abrogate Angiogenesis in Erlich Ascites Tumor Bearing Mice

Author(s): Nanjundaswamy Ashwini, Kyathegowdanadoddi S. Balaji, Bettadahalli L. Sadashivaiah, Toreshettahally R. Swaroop, Shankar Jayarama, Kempegowda Mantelingu* and Kanchugarakoppal S. Rangappa*

Volume 23, Issue 17, 2023

Published on: 07 August, 2023

Page: [1924 - 1931] Pages: 8

DOI: 10.2174/1871520623666230719153257

Price: $65

Abstract

Background: Indazoles are known for their anti-cancer properties.

Objective: The current investigation was on the synthesis and evaluation of novel indazole derivatives for their anticancer properties.

Methods: A series of novel indazoles were synthesized and characterized by IR, NMR and LCMS. We performed cytotoxic studies for all synthesized compounds on different cell lines such as HeLa, MCF-7 and EAC using MTT assay. The lead compound was tested further for its anti-tumor and anti-angiogenic effect on EAT tumor model.

Results: Amongst the series of compounds synthesized, compound KA8 showed potent antiproliferative effect against Hela, MCF-7 and EAC cell lines with IC50 values 10.4 to 11.5 and 13.5 μM respectively. In addition, our compound KA8 significantly decreased the cell viability, body weight, ascites volume and it also showed superior survival ability of mice compared to control groups. Furthermore, it suppressed the formation of neovasculature in the peritoneum of EAT-bearing mice.

Conclusion: The findings reveal that the lead compound KA8 possesses potent anti-tumor and anti-angiogenic properties thereby promising it to be developed as a novel anticancer agent with further mechanistic studies.

Keywords: Indazole, erlich ascites tumor, antiproliferative, peritoneal angiogenesis, apoptosis, derivatives.

Graphical Abstract
[1]
World Health Organization, Global health estimates 2015: deaths by cause, age, sex, by country and by region, 2000–2015., 2016. Available from: https://www.who.int/data/global-health-estimates=
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Choudhari, A.S.; Mandave, P.C.; Deshpande, M.; Ranjekar, P.; Prakash, O. Phytochemicals in cancer treatment: From preclinical studies to clinical practice. Front. Pharmacol., 2020, 10, 1614-1614.
[http://dx.doi.org/10.3389/fphar.2019.01614] [PMID: 32116665]
[4]
Demain, A.L.; Vaishnav, P. Natural products for cancer chemotherapy. Microb. Biotechnol., 2011, 4(6), 687-699.
[http://dx.doi.org/10.1111/j.1751-7915.2010.00221.x] [PMID: 21375717]
[5]
Schmidt, E.V.; Chisamore, M.J.; Chaney, M.F.; Maradeo, M.E.; Anderson, J.; Baltus, G.A.; Pinheiro, E.M.; Uebele, V.N. Assessment of clinical activity of PD-1 checkpoint inhibitor combination therapies reported in clinical trials. JAMA Netw. Open, 2020, 3(2), e1920833-e1920833.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.20833] [PMID: 32049290]
[6]
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[7]
Dua, R.; Shrivastava, S.; Sonwane, S.K.; Srivastava, S.K. Pharmacological significance of synthetic heterocycles scaffold: a review. Adv. Biol. Res., 2011, 5(3), 120-144.
[8]
Thangadurai, A.; Minu, M.; Wakode, S.; Agrawal, S.; Narasimhan, B. Indazole: a medicinally important heterocyclic moiety. Med. Chem. Res., 2012, 21(7), 1509-1523.
[http://dx.doi.org/10.1007/s00044-011-9631-3]
[9]
Wan, Y.; He, S.; Li, W.; Tang, Z. Indazole derivatives: promising anti-tumor agents. Anticancer. Agents Med. Chem., 2018, 18(9), 1228-1234.
[http://dx.doi.org/10.2174/1871520618666180510113822] [PMID: 29745343]
[10]
Cheekavolu, C.; Muniappan, M. In vivo and in vitro anti-inflammatory activity of indazole and its derivatives. J. Clin. Diagn. Res., 2016, 10(9), FF01-FF06.
[http://dx.doi.org/10.7860/JCDR/2016/19338.8465] [PMID: 27790461]
[11]
Al-Bogami, A.S. Mechanochemical synthesis of cyclohexenones and indazoles as potential antimicrobial agents. Res. Chem. Intermed., 2016, 42(6), 5457-5477.
[http://dx.doi.org/10.1007/s11164-015-2379-5]
[12]
Feng, S.; Li, C.; Chen, D.; Zheng, X.; Yun, H.; Gao, L.; Shen, H.C. Discovery of methylsulfonyl indazoles as potent and orally active res-piratory syncytial Virus (RSV) fusion inhibitors. Eur. J. Med. Chem., 2017, 138, 1147-1157.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.032] [PMID: 28772235]
[13]
Khan, I.; Ibrar, A.; Abbas, N. Oxadiazoles as privileged motifs for promising anticancer leads: recent advances and future prospects. Arch. Pharm., 2014, 347(1), 1-20.
[http://dx.doi.org/10.1002/ardp.201300231] [PMID: 24265208]
[14]
Uppulapu, S.K.; Alam, M.J.; Kumar, S.; Banerjee, S.K. Indazole and its derivatives in cardiovascular diseases: overview, current scenario, and future perspectives. Curr. Top. Med. Chem., 2022, 22(14), 1177-1188.
[http://dx.doi.org/10.2174/1568026621666211214151534] [PMID: 34906057]
[15]
Dong, J.; Zhang, Q.; Wang, Z.; Huang, G.; Li, S. Recent advances in the development of indazole‐based anticancer agents. ChemMedChem, 2018, 13(15), 1490-1507.
[http://dx.doi.org/10.1002/cmdc.201800253] [PMID: 29863292]
[16]
Touat, M.; Ileana, E.; Postel-Vinay, S.; André, F.; Soria, J.C. Targeting FGFR signaling in cancer. Clin. Cancer Res., 2015, 21(12), 2684-2694.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2329] [PMID: 26078430]
[17]
van Geel, R.M.J.M.; Beijnen, J.H.; Schellens, J.H.M. Concise drug review: pazopanib and axitinib. Oncologist, 2012, 17(8), 1081-1089.
[http://dx.doi.org/10.1634/theoncologist.2012-0055] [PMID: 22733795]
[18]
Denya, I.; Malan, S.F.; Joubert, J. Indazole derivatives and their therapeutic applications: a patent review (2013-2017). Expert Opin. Ther. Pat., 2018, 28(6), 441-453.
[http://dx.doi.org/10.1080/13543776.2018.1472240] [PMID: 29718740]
[19]
Roopashree, R.; Mohan, C.D.; Swaroop, T.R.; Jagadish, S.; Rangappa, K.S. Synthesis, characterization and in vivo biological evaluation of novel benzimidazoles as potential anticancer agents. Asian J. Pharm. Clin. Res., 2014, 5(7), 309-313.
[20]
Ray, U.; Raul, S.K.; Gopinatha, V.K.; Ghosh, D.; Rangappa, K.S.; Mantelingu, K.; Raghavan, S.C. Identification and characterization of novel SCR7-based small-molecule inhibitor of DNA end-joining, SCR130 and its relevance in cancer therapeutics. Mol. Carcinog., 2020, 59(6), 618-628.
[http://dx.doi.org/10.1002/mc.23186] [PMID: 32189406]
[21]
Hegde, M.; Mantelingu, K.; Swarup, H.A.; Pavankumar, C.S.; Qamar, I.; Raghavan, S.C.; Rangappa, K.S. Novel PARP inhibitors sensitize human leukemic cells in an endogenous PARP activity dependent manner. RSC Advances, 2016, 6(8), 6308-6319.
[http://dx.doi.org/10.1039/C5RA19150E]
[22]
Rakesh, K.S.; Jagadish, S.; Swaroop, T.R.; Mohan, C.D.; Ashwini, N.; Harsha, K.B.; Zameer, F.; Girish, K.S.; Rangappa, K.S. Anticancer activity of 2,4-disubstituted thiophene derivatives: dual inhibitors of lipoxygenase and cyclooxygenase. Med. Chem., 2015, 11(5), 462-472.
[http://dx.doi.org/10.2174/1573406411666141210141918] [PMID: 25494807]
[23]
Hegde, M.; Mantelingu, K.; Pandey, M.; Pavankumar, C.S.; Rangappa, K.S.; Raghavan, S.C. Combinatorial study of a novel poly (ADP-ribose) polymerase inhibitor and an HDAC inhibitor, SAHA, in leukemic cell lines. Target. Oncol., 2016, 11(5), 655-665.
[http://dx.doi.org/10.1007/s11523-016-0441-x] [PMID: 27188390]
[24]
Rakesh, K.S.; Jagadish, S.; Balaji, K.S.; Zameer, F.; Swaroop, T.R.; Mohan, C.D.; Jayarama, S.; Rangappa, K.S. 3,5-Disubstituted isoxazole derivatives: potential inhibitors of inflammation and cancer. Inflammation, 2016, 39(1), 269-280.
[http://dx.doi.org/10.1007/s10753-015-0247-5] [PMID: 26363638]
[25]
Preethi, S.D.; Balaji, K.S.; Prasanna, D.S.; Swaroop, T.R.; Shankar, J.; Rangappa, K.S.; Lokesh, S. Synthesis, characterization of 4-anilino-6,7-dimethoxyquinazoline derivatives as potential anti-angionic agents. Anticancer. Agents Med. Chem., 2017, 17, 1931-1941.
[26]
De Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer, 2017, 17(8), 457-474.
[http://dx.doi.org/10.1038/nrc.2017.51] [PMID: 28706266]
[27]
Ribatti, D. targeting angiogenesis in neuroblastoma. In: Neuroblastoma; Academic Press: Cambridge.: MA, USA, 2019.
[28]
Kerr, J F R.; Wyllie, A.H.; Currie, A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer, 1972, 26(4), 239-257.
[http://dx.doi.org/10.1038/bjc.1972.33] [PMID: 4561027]
[29]
Prabhakar, B.T.; Khanum, S.A.; Jayashree, K.; Salimath, B.P.; Shashikanth, S. Anti-tumor and proapoptotic effect of novel synthetic benzophenone analogues in Ehrlich ascites tumor cells. Bioorg. Med. Chem., 2006, 14(2), 435-446.
[http://dx.doi.org/10.1016/j.bmc.2005.08.039] [PMID: 16214348]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy