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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Synthesis, Biological Investigation and Docking Study of Novel Chromen Derivatives as Anti-Cancer Agents

Author(s): Pritam N. Dube, Nikhil S. Sakle, Sachin A. Dhawale, Shweta A. More and Santosh N. Mokale*

Volume 19, Issue 9, 2019

Page: [1150 - 1160] Pages: 11

DOI: 10.2174/1871520619666190307121145

Price: $65

Abstract

Background: According to the latest global cancer data, cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Among that female breast cancer ranks as the fifth leading cause of death (627000 deaths, 6.6%). The main causative factor involved in breast cancer development and progression is the Estrogen Receptor (ER) which is the essential target for anti-cancer drug discovery. Since millennia ER-α has been considered as an oncology mark for the treatment of breast cancer.

Methods: A series of novel 6-methyl-3-(3-oxo-1-phenyl-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)propyl)-2Hchromen- 2-one was designed, synthesized and screened for their anti-breast cancer activity against estrogen receptor-positive MCF-7, ZR-75-1 and negative MDA-MB-435 human breast cancer cell lines. Estrogen level of all the potent cytotoxic compounds were measured on day 30 of intoxication was compared with the control and N-methyl-N-nitrosourea (MNU) group. The docking study was performed to predict binding orientation towards the estrogen receptor-α.

Results: Among the synthesized compounds C-3, C-5 and C-15 were showing potent cytotoxicity against estrogen receptor-positive MCF-7. The potent cytotoxic compounds C-3, C-5 and C-15 were further evaluated for in vivo anti-cancer activity by MNU induced mammary carcinoma in female sprague-dawley rats. The in vivo anticancer activity result shows that the compound C-5 has protuberant affinity towards estrogen receptor as standard TAM (Tamoxifen). The docking of the synthesized chromen derivatives showed interaction modes comparable to that of the co-crystallized ligands.

Conclusion: The designed class has very promising starting point for the development and further improvement in anti-breast cancer class of drugs.

Keywords: Breast cancer, SERMs, chalcone, docking, novel chromene derivatives, anti-cancer agents.

Graphical Abstract
[1]
Qiao, A.; Gu, F.; Guo, X.; Zhang, X.; Fu, L. Breast cancer-associated fibroblasts: Their roles in tumor initiation, progression and clinical applications. Front. Med., 2016, 10(1), 33-40.
[2]
Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics 2016. CA Cancer J. Clin., 2016, 66(4), 271-289.
[3]
Baskar, R.; Lee, K.A.; Yeo, R.; Yeoh, K.W. Cancer and radiation therapy: Current advances and future directions. Int. J. Med. Sci., 2012, 9(3), 193-199.
[4]
Dias, D.A.; Urban, S.; Roessner, U. A historical overview of natural products in drug discovery. Metabolites, 2012, 2(2), 303-336.
[5]
Cragg, G.M.; Newman, D.J. Natural products: A continuing source of novel drug leads. Biochim. Biophys. Acta, 2013, 1830(6), 3670-3695.
[6]
Demain, A.L.; Vaishnav, P. Natural products for cancer chemotherapy. Microb. Biotechnol., 2011, 4(6), 687-699.
[7]
Raffa, D.; Maggio, B.; Raimondi, M.V.; Plescia, F.; Daidone, G. Recent discoveries of anticancer flavonoids. Eur. J. Med. Chem., 2017, 142, 213-228.
[8]
Mahapatra, D.K.; Bharti, S.K.; Asati, V. Anti-cancer chalcones: Structural and molecular target perspectives. Eur. J. Med. Chem., 2015, 98, 69-114.
[9]
Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur. J. Med. Chem., 2015, 102, 611-630.
[10]
Karthikeyan, C.; Moorthy, N.S.; Ramasamy, S.; Vanam, U.; Manivannan, E.; Karunagaran, D.; Trivedi, P. Advances in chalcones with anticancer activities. Recent Patents Anticancer Drug Discov., 2015, 10(1), 97-115.
[11]
Obr, A.E.; Edwards, D.P. The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol. Cell. Endocrinol., 2012, 357(1-2), 4-17.
[12]
Hanstein, B.; Djahansouzi, S.; Dall, P.; Beckmann, M.W.; Bender, H.G. Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer. Eur. J. Endocrinol., 2004, 150(3), 243-255.
[13]
Alvarado, A.; Lopes, A.C.; Faustino-Rocha, A.I.; Cabrita, A.M.S.; Ferreira, R.; Oliveira, P.A.; Colaço, B. Prognostic factors in MNU and DMBA-induced mammary tumors in female rats. Pathol. Res. Pract., 2017, 213(5), 441-446.
[14]
Dube, P.N.; Waghmare, M.N.; Mokale, S.N. Synthesis, in vitro, and in vivo biological evaluation and molecular docking analysis of novel 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl) propyl)-2H-chromen-2-one derivatives as anti-breast cancer agents. Chem. Biol. Drug Des., 2016, 87(4), 608-617.
[15]
Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc., 2006, 1(3), 1112-1116.
[16]
Skehn, P.; Storeng, R.; Scudiero, A.; Monks, J.; McMohan, D.; Vistica, D.; Jonathan, T.W.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[17]
Mokale, S.N.; Begum, A.; Sakle, N.S.; Shelke, V.R.; Bhavale, S.A. Design, synthesis and anticancer screening of 3-(3-(substituted phenyl) acryloyl)-2H-chromen-2ones as selective anti-breast cancer agent. Biomed. Pharmacother., 2017, 89, 966-972.
[18]
Russo, J.; Russo, I.H. Atlas and histologic classification of tumors of the rat mammary gland. J. Mammary Gland Biol. Neoplasia, 2000, 5(2), 187-200.
[19]
Dube, P.N.; Mokale, S.N. Design and synthesis of some novel estrogen receptor modulators as anti-breast cancer Agents: In vitro & in vivo screening, docking analysis. Anticancer. Agents Med. Chem., 2016, 16(11), 1461-1467.
[20]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49, 6177-6196.
[21]
Boopalan, T.; Arumugam, A.; Parada, J.; Saltzstein, E.; Lakshmanaswamy, R. Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis. Cancer Sci., 2015, 106(1), 25-33.
[22]
Kariagina, A.; Xie, J.; Langohr, I.M.; Opreanu, R.C.; Basson, M.D.; Haslam, S.Z. Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers. Horm. Cancer, 2013, 4(6), 381-390.

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