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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Synthesis, and In-silico Studies of Indole-chalcone Derivatives Targeting Estrogen Receptor Alpha (ER-α) for Breast Cancer

Author(s): Rahul Charudatta Choudhari, Kamalpreet Kaur, Agnidipta Das and Vikas Jaitak*

Volume 20, Issue 5, 2024

Published on: 04 October, 2023

Page: [640 - 652] Pages: 13

DOI: 10.2174/0115734099263650230926053750

Price: $65

Abstract

Background: Breast cancer is the prominent reason of death in women worldwide, and the cases are increasing day by day. There are many FDA-approved drugs for treating breast cancer. Due to drug resistance, and problems in selectivity, there is a need to develop more effective agents with few side effects. Indole derivatives have demonstrated significant pharmacological potential as anti-breast cancer agents. Further, chalcone derivatives incorporating heterocyclic scaffolds play a significant role in medicine. Indole-chalcone-based compounds offer the potential for improved biological activity and enhanced drug-like properties. It prompted us to explore the synthesis of Indole-Chalcone derivatives targeting estrogen receptor alpha (ER-α) to discover potent anti-breast cancer agents.

Objectives: To synthesize indole-chalcone derivatives and study their binding interactions for ER-α protein by molecular docking for breast cancer treatment.

Methods: In this study, indole-chalcone derivatives have been synthesized using conventional heating. With the help of Schrodinger software, molecular interaction as well as ADME (Adsorption, Distribution, Metabolism, and Excretion) studies of the compounds were conducted.

Results: Among all the synthesized compounds, four compounds (1, 2, 3, and 4) showed better docking scores (-10.24 kcal/mol, -10.15 kcal/mol, -9.40 kcal/mol, -9.29 kcal/mol, respectively) than the standard tamoxifen (-8.43 kcal/mol).

Conclusion: From In-silico studies, we can conclude that four compounds from the synthesized series fit into the active site of ER-α. ADME properties of synthesized derivatives were found in the acceptable range. In the future, these compounds can be further explored for biological activity.

Keywords: Indole-chalcone, anti-breast cancer, anti-cancer, estrogen receptor, in-silico, ADME.

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[1]
Nurmik, M.; Ullmann, P.; Rodriguez, F.; Haan, S.; Letellier, E. In search of definitions: Cancer‐associated fibroblasts and their markers. Int. J. Cancer, 2020, 146(4), 895-905.
[http://dx.doi.org/10.1002/ijc.32193] [PMID: 30734283]
[2]
Rawat, A.; Vijaya Bhaskar Reddy, A. Recent advances on anticancer activity of coumarin derivatives. Eur. J. Med. Chem. Rep., 2022, 5, 100038.
[http://dx.doi.org/10.1016/j.ejmcr.2022.100038]
[3]
Insan, M.; Jaitak, V. New approaches to target cancer stem cells: Current scenario. Mini Rev. Med. Chem., 2014, 14(1), 20-34.
[http://dx.doi.org/10.2174/13895575113136660107] [PMID: 24195662]
[4]
Matthews, H.K.; Bertoli, C.; de Bruin, R.A.M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol., 2022, 23(1), 74-88.
[http://dx.doi.org/10.1038/s41580-021-00404-3] [PMID: 34508254]
[5]
Poorkiani, M.; Abbaszadeh, A.; Hazrati, M.; Jafari, P.; Sadeghi, M.; Mohammadianpanah, M. The effect of rehabilitation on quality of life in female breast cancer survivors in Iran. Indian J. Med. Paediatr. Oncol., 2010, 31(4), 105-109.
[http://dx.doi.org/10.4103/0971-5851.76190] [PMID: 21584214]
[6]
Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin., 2023, 73(1), 17-48.
[http://dx.doi.org/10.3322/caac.21763] [PMID: 36633525]
[7]
Cowin, P.; Rowlands, T.M.; Hatsell, S.J. Cadherins and catenins in breast cancer. Curr. Opin. Cell Biol., 2005, 17(5), 499-508.
[http://dx.doi.org/10.1016/j.ceb.2005.08.014] [PMID: 16107313]
[8]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates 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]
[9]
Emam, S.M.; Rayes, S.M.E.; Ali, I.A.I.; Soliman, H.A.; Nafie, M.S. Synthesis of phthalazine-based derivatives as selective anti-breast cancer agents through EGFR-mediated apoptosis: In vitro and in silico studies. BMC Chem., 2023, 17(1), 90.
[http://dx.doi.org/10.1186/s13065-023-00995-2] [PMID: 37501139]
[10]
Walker, S.; Hyde, C.; Hamilton, W. Risk of breast cancer in symptomatic women in primary care: A case–control study using electronic records. Br. J. Gen. Pract., 2014, 64(629), e788-e793.
[http://dx.doi.org/10.3399/bjgp14X682873] [PMID: 25452544]
[11]
Tasmuth, T.; Smitten, K.; Hietanen, P.; Kataja, M.; Kalso, E. Pain and other symptoms after different treatment modalities of breast cancer. Ann. Oncol., 1995, 6(5), 453-459.
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a059215] [PMID: 7669710]
[12]
Bish, A.; Ramirez, A.; Burgess, C.; Hunter, M. Understanding why women delay in seeking help for breast cancer symptoms. J. Psychosom. Res., 2005, 58(4), 321-326.
[http://dx.doi.org/10.1016/j.jpsychores.2004.10.007] [PMID: 15992567]
[13]
Wrensch, M.R.; Petrakis, N.L.; Miike, R.; King, E.B.; Chew, K.; Neuhaus, J.; Lee, M.M.; Rhys, M. Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. J. Natl. Cancer Inst., 2001, 93(23), 1791-1798.
[http://dx.doi.org/10.1093/jnci/93.23.1791] [PMID: 11734595]
[14]
Langford, D.J.; Schmidt, B.; Levine, J.D.; Abrams, G.; Elboim, C.; Esserman, L.; Hamolsky, D.; Mastick, J.; Paul, S.M.; Cooper, B.; Kober, K.; Dodd, M.; Dunn, L.; Aouizerat, B.; Miaskowski, C. Preoperative breast pain predicts persistent breast pain and disability after breast cancer surgery. J. Pain Symptom Manage., 2015, 49(6), 981-994.
[http://dx.doi.org/10.1016/j.jpainsymman.2014.11.292] [PMID: 25527442]
[15]
Lee, J.; Park, W.; Choi, D.H.; Huh, S.J.; Kim, I.R.; Kang, D.; Cho, J. Patient-reported symptoms of radiation dermatitis during breast cancer radiotherapy: A pilot study. Qual. Life Res., 2017, 26(7), 1713-1719.
[http://dx.doi.org/10.1007/s11136-017-1526-4] [PMID: 28238091]
[16]
Katsura, C.; Ogunmwonyi, I.; Kankam, H.K.N.; Saha, S. Breast cancer: Presentation, investigation and management. Br. J. Hosp. Med., 2022, 83(2), 1-7.
[http://dx.doi.org/10.12968/hmed.2021.0459] [PMID: 35243878]
[17]
Hamood, R.; Hamood, H.; Merhasin, I.; Keinan-Boker, L. Chronic pain and other symptoms among breast cancer survivors: Prevalence, predictors, and effects on quality of life. Breast Cancer Res. Treat., 2018, 167(1), 157-169.
[http://dx.doi.org/10.1007/s10549-017-4485-0] [PMID: 28861642]
[18]
Schou Bredal, I.; Smeby, N.A.; Ottesen, S.; Warncke, T.; Schlichting, E. Chronic pain in breast cancer survivors: Comparison of psychosocial, surgical, and medical characteristics between survivors with and without pain. J. Pain Symptom Manage., 2014, 48(5), 852-862.
[http://dx.doi.org/10.1016/j.jpainsymman.2013.12.239] [PMID: 24703940]
[19]
Weaver, D.L. Pathology evaluation of sentinel lymph nodes in breast cancer: Protocol recommendations and rationale. Mod. Pathol., 2010, 23(2), S26-S32.
[http://dx.doi.org/10.1038/modpathol.2010.36] [PMID: 20436499]
[20]
Van Trappen, P.; Serreyn, R.; Elewaut, A.E.; Cocquyt, V.; Van Belle, S. Abdominal pain with anorexia in patients with breast carcinoma. Ann. Oncol., 1998, 9(11), 1243-1245.
[http://dx.doi.org/10.1023/A:1008287007819] [PMID: 9862056]
[21]
Koo, M.M.; von Wagner, C.; Abel, G.A.; McPhail, S.; Rubin, G.P.; Lyratzopoulos, G. Typical and atypical presenting symptoms of breast cancer and their associations with diagnostic intervals: Evidence from a national audit of cancer diagnosis. Cancer Epidemiol., 2017, 48, 140-146.
[http://dx.doi.org/10.1016/j.canep.2017.04.010] [PMID: 28549339]
[22]
Weigelt, B.; Reis-Filho, J.S. Histological and molecular types of breast cancer: Is there a unifying taxonomy? Nat. Rev. Clin. Oncol., 2009, 6(12), 718-730.
[http://dx.doi.org/10.1038/nrclinonc.2009.166] [PMID: 19942925]
[23]
Colditz, G.A. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J. Natl. Cancer Inst., 1998, 90(11), 814-823.
[http://dx.doi.org/10.1093/jnci/90.11.814] [PMID: 9625169]
[24]
Clemons, M.; Goss, P. Estrogen and the risk of breast cancer. N. Engl. J. Med., 2001, 344(4), 276-285.
[http://dx.doi.org/10.1056/NEJM200101253440407] [PMID: 11172156]
[25]
de Oliveira, V.M.; Dias, M.M.G.; Avelino, T.M.; Videira, N.B.; da Silva, F.B.; Doratioto, T.R.; Whitford, P.C.; Leite, V.B.P.; Figueira, A.C.M. pH and the breast cancer recurrent mutation d538g affect the process of activation of estrogen receptor α. Biochemistry, 2022, 61(6), 455-463.
[http://dx.doi.org/10.1021/acs.biochem.1c00806] [PMID: 35238537]
[26]
Rouzier, R.; Perou, C.M.; Symmans, W.F.; Ibrahim, N.; Cristofanilli, M.; Anderson, K.; Hess, K.R.; Stec, J.; Ayers, M.; Wagner, P.; Morandi, P.; Fan, C.; Rabiul, I.; Ross, J.S.; Hortobagyi, G.N.; Pusztai, L. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer Res., 2005, 11(16), 5678-5685.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2421] [PMID: 16115903]
[27]
TilakVijay, J.; Vivek Babu, K.; Uma, A. Virtual screening of novel compounds as potential ERα; inhibitors. Bioinformation, 2019, 15(5), 321-332.
[http://dx.doi.org/10.6026/97320630015321] [PMID: 31249434]
[28]
Tang, Z.R.; Zhang, R.; Lian, Z.X.; Deng, S.L.; Yu, K. Estrogen-receptor expression and function in female reproductive disease. Cells, 2019, 8(10), 1123.
[http://dx.doi.org/10.3390/cells8101123] [PMID: 31546660]
[29]
Hewitt, S.C.; Winuthayanon, W.; Korach, K.S. What’s new in estrogen receptor action in the female reproductive tract. J. Mol. Endocrinol., 2016, 56(2), R55-R71.
[http://dx.doi.org/10.1530/JME-15-0254] [PMID: 26826253]
[30]
Das, S.; Kulkarni, S.; Singh, Y.; Kumar, P.; Thareja, S. Selective Estrogen Receptor Modulators (SERMs) for the treatment of ER+ breast cancer: An overview. J. Mol. Struct., 2022, 1270, 133853.
[http://dx.doi.org/10.1016/j.molstruc.2022.133853]
[31]
Jaitak, V.; Das, A.; Lavanya, K.J.; Nandini; Kaur, K. Effectiveness of selective estrogen receptor modulators in breast cancer therapy: An update. Curr. Med. Chem., 2023, 30(29), 3287-3314.
[http://dx.doi.org/10.2174/0929867329666221006110528] [PMID: 36201273]
[32]
Paterni, I.; Granchi, C.; Katzenellenbogen, J.A.; Minutolo, F. Estrogen receptors alpha (ERα;) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids, 2014, 90, 13-29.
[http://dx.doi.org/10.1016/j.steroids.2014.06.012] [PMID: 24971815]
[33]
Moon, Y.J.; Zhang, Z.; Bang, I.H.; Kwon, O.K.; Yoon, S.J.; Kim, J.R.; Lee, S.; Bae, E.J.; Park, B.H. Sirtuin 6 in preosteoclasts suppresses age- and estrogen deficiency-related bone loss by stabilizing estrogen receptor α. Cell Death Differ., 2019, 26(11), 2358-2370.
[http://dx.doi.org/10.1038/s41418-019-0306-9] [PMID: 30787391]
[34]
Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.; Howard, B.V.; Johnson, K.C.; Kotchen, J.M.; Ockene, J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trial. JAMA, 2002, 288(3), 321-333.
[http://dx.doi.org/10.1001/jama.288.3.321] [PMID: 12117397]
[35]
Suliphuldevara Mathada, B.; Gunavanthrao Yernale, N.; Basha, J.N. The multi‐pharmacological targeted role of indole and its derivatives: A review. ChemistrySelect, 2023, 8(1), e202204181.
[http://dx.doi.org/10.1002/slct.202204181]
[36]
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89, 103021.
[http://dx.doi.org/10.1016/j.bioorg.2019.103021] [PMID: 31176854]
[37]
Dorababu, A. Indole - a promising pharmacophore in recent antiviral drug discovery. RSC Med. Chem., 2020, 11(12), 1335-1353.
[http://dx.doi.org/10.1039/D0MD00288G] [PMID: 34095843]
[38]
Sidhu, J.S.; Singla, R.; Mayank; Jaitak, V. Indole derivatives as anticancer agents for breast cancer therapy: A review. Anticancer. Agents Med. Chem., 2015, 16(2), 160-173.
[http://dx.doi.org/10.2174/1871520615666150520144217] [PMID: 25991424]
[39]
Kaur, K.; Jaitak, V. Recent development in indole derivatives as anticancer agents for breast cancer. Anticancer. Agents Med. Chem., 2019, 19(8), 962-983.
[http://dx.doi.org/10.2174/1871520619666190312125602] [PMID: 30864529]
[40]
Devi, N.; Kaur, K.; Biharee, A.; Jaitak, V. Recent development in indole derivatives as anticancer agent: A mechanistic approach. Anticancer. Agents Med. Chem., 2021, 21(14), 1802-1824.
[http://dx.doi.org/10.2174/1871520621999210104192644] [PMID: 33397272]
[41]
Singla, R.; Gupta, K.B.; Upadhyay, S.; Dhiman, M.; Jaitak, V. Design, synthesis and biological evaluation of novel indole-benzimidazole hybrids targeting estrogen receptor alpha (ER-α;). Eur. J. Med. Chem., 2018, 146, 206-219.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.051] [PMID: 29407951]
[42]
Singla, R.; Gupta, K.B.; Upadhyay, S.; Dhiman, M.; Jaitak, V. Design, synthesis and biological evaluation of novel indole-xanthendione hybrids as selective estrogen receptor modulators. Bioorg. Med. Chem., 2018, 26(1), 266-277.
[http://dx.doi.org/10.1016/j.bmc.2017.11.040] [PMID: 29198894]
[43]
Singla, R.; Prakash, K.; Bihari Gupta, K.; Upadhyay, S.; Dhiman, M.; Jaitak, V. Identification of novel indole based heterocycles as selective estrogen receptor modulator. Bioorg. Chem., 2018, 79, 72-88.
[http://dx.doi.org/10.1016/j.bioorg.2018.04.002] [PMID: 29723744]
[44]
Jiang, B.E.; Hu, J.; Liu, H.; Liu, Z.; Wen, Y.; Liu, M.; Zhang, H.K.; Pang, X.; Yu, L.F. Design, synthesis, and biological evaluation of indole-based hydroxamic acid derivatives as histone deacetylase inhibitors. Eur. J. Med. Chem., 2022, 227, 113893.
[http://dx.doi.org/10.1016/j.ejmech.2021.113893] [PMID: 34656899]
[45]
Laaroussi, H.; Ding, Y.; Teng, Y.; Deschamps, P.; Vidal, M.; Yu, P.; Broussy, S. Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents. Eur. J. Med. Chem., 2020, 202, 112561.
[http://dx.doi.org/10.1016/j.ejmech.2020.112561] [PMID: 32711231]
[46]
Shu, B.; Yu, Q.; Hu, D.; Che, T.; Zhang, S.; Li, D. Synthesis and biological evaluation of novel indole-pyrazoline hybrid derivatives as potential topoisomerase 1 inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(4), 126925.
[http://dx.doi.org/10.1016/j.bmcl.2019.126925] [PMID: 31901379]
[47]
Dadashpour, S.; Emami, S. Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur. J. Med. Chem., 2018, 150, 9-29.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.065] [PMID: 29505935]
[48]
Komoto, T.T.; Nishimura, F.G.; Evangelista, A.F.; de Freitas, A.J.A.; da Silva, G.; Silva, W.A.; Peronni, K.; Marques, M.M.C.; Marins, M.; Fachin, A.L. Exploring the therapeutic potential of trans-chalcone: Modulation of micrornas linked to breast cancer progression in MCF-7 cells. Int. J. Mol. Sci., 2023, 24(13), 10785.
[http://dx.doi.org/10.3390/ijms241310785] [PMID: 37445965]
[49]
Mezgebe, K.; Melaku, Y.; Mulugeta, E. Synthesis and pharmacological activities of chalcone and its derivatives bearing n -heterocyclic scaffolds: A review. ACS Omega, 2023, 8(22), 19194-19211.
[http://dx.doi.org/10.1021/acsomega.3c01035] [PMID: 37305270]
[50]
Michalkova, R.; Kello, M.; Kudlickova, Z.; Gazdova, M.; Mirossay, L.; Mojzisova, G.; Mojzis, J. Programmed cell death alterations mediated by synthetic indole chalcone resulted in cell cycle arrest, dna damage, apoptosis and signaling pathway modulations in breast cancer model. Pharmaceutics, 2022, 14(3), 503.
[http://dx.doi.org/10.3390/pharmaceutics14030503] [PMID: 35335879]
[51]
Robinson, M.W.; Overmeyer, J.H.; Young, A.M.; Erhardt, P.W.; Maltese, W.A. Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death. J. Med. Chem., 2012, 55(5), 1940-1956.
[http://dx.doi.org/10.1021/jm201006x] [PMID: 22335538]
[52]
Cong, H.; Zhao, X.; Castle, B.T.; Pomeroy, E.J.; Zhou, B.; Lee, J.; Wang, Y.; Bian, T.; Miao, Z.; Zhang, W.; Sham, Y.Y.; Odde, D.J.; Eckfeldt, C.E.; Xing, C.; Zhuang, C. An indole-chalcone inhibits multidrug-resistant cancer cell growth by targeting microtubules. Mol. Pharm., 2018, 15(9), 3892-3900.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00359] [PMID: 30048137]
[53]
Badria, F.A.; Soliman, S.M.; Atef, S.; Islam, M.S.; Al-Majid, A.M.; Dege, N.; Ghabbour, H.A.; Ali, M.; El-Senduny, F.F.; Barakat, A. Anticancer indole-based chalcones: A structural and theoretical analysis. Molecules, 2019, 24(20), 3728.
[http://dx.doi.org/10.3390/molecules24203728] [PMID: 31623155]
[54]
Yan, J.; Chen, J.; Zhang, S.; Hu, J.; Huang, L.; Li, X. Synthesis, evaluation, and mechanism study of novel indole-chalcone derivatives exerting effective antitumor activity through microtubule destabilization in vitro and in vivo. J. Med. Chem., 2016, 59(11), 5264-5283.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00021] [PMID: 27149641]
[55]
Mayank; Jaitak, V. Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy. Comput. Biol. Chem., 2016, 62, 145-154.
[http://dx.doi.org/10.1016/j.compbiolchem.2015.08.001] [PMID: 26278973]
[56]
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K.; Feng, Z.; Gilliland, G.L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J.D.; Zardecki, C. The protein data bank. Acta Crystallogr. D Biol. Crystallogr., 2002, 58(Pt 6 No 1), 899-907.
[57]
Sahayarayan, J.J.; Rajan, K.S.; Vidhyavathi, R.; Nachiappan, M.; Prabhu, D.; Alfarraj, S.; Arokiyaraj, S.; Daniel, A.N. In-silico protein-ligand docking studies against the estrogen protein of breast cancer using pharmacophore based virtual screening approaches. Saudi J. Biol. Sci., 2021, 28(1), 400-407.
[http://dx.doi.org/10.1016/j.sjbs.2020.10.023] [PMID: 33424323]

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