Abstract
A series of novel-substituted chalcone analogs were synthesized and evaluated for antiproliferative activity against estrogen receptor-positive MCF-7 breast cancer cell lines. Among the synthesized derivatives 4a, 5a, 5b, 5c, 5e, 5′a, and 5′d show good antiproliferative activity as compared to standard tamoxifen. The study highlighted the advantage of introducing the amine side chain pharmacophore in substituted chalcone enhances the anticancer potential. The study also suggests that these analogs can serve as better therapeutic agents against breast cancer and can provide starting point for building more potent analogs in future. The binding mechanism and ADME properties of target compounds were analysed using Schrödinger software.
Similar content being viewed by others
References
Batovska DI, Todorova TI (2010) Trends in utilization of the pharmacological potential of chalcones. Curr Clin Pharmacol 5:1–29
Björnström L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19:833–842
Bray F, Ren JS, Masuver E, Ferlay J (2013) Estimates of global cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132:1133–1145
Cancer Trends Progress Report—2009/2010 update (2012) WHO website. http://www.who.int/cancer/en and http://progressreport.cancer.gov. Accessed 10 Dec 2013.
Cummings J, Ward TH, Ranson M, Dive C (2004) Apoptosis pathway-targeted drugs—from the bench to the clinic. Biochim Biophys Acta 1705:53–66
DeConti RC (2012) Chemotherapy of squamous cell carcinoma of the skin. Semin Oncol 39:145–149
Deroo BJ, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116:561–570
Ding X, Bai D, Qian J (2014) Novel cyclotides from Hedyotis biflora inhibit proliferation and migration of pancreatic cancer cell in vitro and in vivo. Med Chem Res 23:1406–1413
Dube PN, Bule SS, Kumbhare MR, Dighe PR, Ushir YV (2014a) Synthesis of novel 5-methyl pyrazol-3-one derivatives and their in vitro Cytotoxic Evaluation. Med Chem Res. doi:10.1007/s00044-014-1201-z
Dube PN, Bule SS, Mokale SN, Kumbhare MR, Dighe PR, Ushir YV (2014b) Synthesis and biological evaluation of substituted 5-methyl-2-phenyl-1H-pyrazol-3(2H)-one derivatives as selective COX-2 inhibitors: molecular docking study. Chem Biol Drug Des. doi:10.1111/cbdd.12324
Dube PN, Mokale SN, Datar P (2014c) CoMFA and docking study of 2, N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as novel PfDHFR enzyme inhibitors for antimalarial activity. Bull Fac Pharm Cairo Univ 52:125–134
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2012) GLOBOCAN 2012v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749
Glass AG, Lacey JV, Carreon JD, Hoover RNJ (2007) Breast cancer incidence, 1980–2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 99:1152–1161
Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N (2009) Triple-negative breast cancer—current status and future directions. Ann Oncol 20:1913–1927
International Agency for Research on Cancer, Lyon, France (2013). http://globocan.iarc.fr. Accessed 2 July 2014.
Irvin WJ, Carey LA (2008) What is triple-negative breast cancer? Eur J Cancer 44:2799–2805
Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, Grove JR (1999) MDCK (Madin-Darby canine kidney) cells: a tool for membrane permeability screening. J Pharm Sci 88:28–33
Johnston SRD, Ford H, Ross P, Brighton D, Wood M (2005) The Royal Marsden Hospital hand book of cancer chemotherapy. Elsevier Churchill Livingstone, London, pp 1–17
Kashid AM, Dube PN, Alkutkar PG, Bothara KG, Mokale SN, Dhawale SC (2013) Synthesis, biological activity and ADME prediction of new series of benzylindole derivatives as novel antiHIV-1, antifungal and antibacterial agents. Med Chem Res 22:4633–4640
Katzenellenbogen BS (2002) Defining the “S” in SERMs. J Appl Sci 295:2380–2381
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26
Lokwani DK, Sarkate AP, Shinde DB (2013) 3D-QSAR and docking studies of benzoyl urea derivatives as tubulin-binding agents for antiproliferative activity. Med Chem Res 22:1415–1425
Maestro, version 9.3, Schrödinger, LLC, New York, NY, 2012.
Mareel M, Leroy A (2003) Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 83:337–376
Marin JJ, Sanchez de Medina F, Castaño B, Bujanda L, Romero MR, Augustin M-O, Moral-Avila RD, Briz O (2012) Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. Drug Metab Rev 44:148–172
Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR (2006) Anticancer activities of novel chalcone and bis-chalcone derivatives. Bioorg Med Chem 14:3491–3495
Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Boyd MR (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer 83:757–766
Nelson G, Alam MA, Atkinson T, Gurrapu S, Kumar JS, Bicknese C, Johnson JL, Williams M (2013) Synthesis and evaluation of p-N,N-dialkyl-substituted chalcones as anti-cancer agents. Med Chem Res 22:4610–4614
Orlikova B, Tasdemir D, Golais F, Dicato M, Diederich M (2011) Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes Nutr 6:125–147
QikProp, version 3.5, Schrödinger, LLC, New York, NY, 2012.
Reis-Filho JS, Tutt AN (2008) Triple negative tumours: a critical review. Histopathology 52:108–118
Sahu NK, Balbhadra SS, Choudhary J, Kohli DV (2012) Exploring pharmacological significance of chalcone scaffold: a review. Curr Med Chem 19:209–225
Shagufta Srivastava AK, Sharma R, Mishra R, Balapure AK, Murthy P, Panda G (2006) Substituted phenanthrenes with basic amino side chains: a new series of anti-breast cancer agents. Bioorg Med Chem 14:1497–1505
Shenvi S, Kumar K, Hatti KS, Rijesh K, Diwakar L, Reddy GC (2013) Synthesis, anticancer and antioxidant activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde: structure–activity relationship. Eur J Med Chem 62:435–442
Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29
Skehn P, Storeng R, Scudiero A, Monks J, McMohan D, Vistica D, Jonathan TW, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112
Tanwar O, Marella A, Shrivastava S, Alam MM, Akhtar M (2013) Pharmacophore model generation and 3D-QSAR analysis of N-acyl and N-aroylpyrazolines for enzymatic and cellular B-Raf kinase inhibition. Med Chem Res 22:2174–2187
Wei BL, Teng CH, Wang JP, Won SJ, Lin CN (2007) Synthetic 2′,5′-dimethoxychalcones as G2/M arrest-mediated apoptosis-inducing agents and inhibitors of nitric oxide production in rat macrophages. Eur J Med Chem 42:660–668
Weschel J, Haglund K, Haugsten EM (2011) Fibroblast growth factors and their receptors in cancer. Biochem J 437:199–213
Acknowledgments
The authors are thankful to Tata Memorial Centre-Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) Kharghar, Navi Mumbai for in-vitro assay against breast cancer activity. This work was supported by the Department of Science and Technology (DST), New Delhi, India (Project File No. SR/FT/LS-132/2012 & Sanction Diary No. SERB/F/4302/2012-13).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mokale, S.N., Dube, P.N., Bhavale, S.A. et al. Synthesis, in-vitro screening, and docking analysis of novel pyrrolidine and piperidine-substituted ethoxy chalcone as anticancer agents. Med Chem Res 24, 1842–1856 (2015). https://doi.org/10.1007/s00044-014-1266-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-014-1266-8