Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64421610.2174/0115734099263650230926053750ChemistryResearch ArticleSynthesis, and In-silico Studies of Indole-chalcone Derivatives Targeting Estrogen Receptor Alpha (ER-α) for Breast CancerChoudhariRahulinfo@benthamscience.netKaurKamalpreetinfo@benthamscience.netDasAgnidiptainfo@benthamscience.netJaitakVikasinfo@benthamscience.netDepartment of Pharmaceutical Sciences and Natural Products, Central University of Punjab0105202420564065207012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644216

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.

Indole-chalconeanti-breast canceranti-cancerestrogen receptorin-silicoADME.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. doi: 10.1002/ijc.32193 PMID: 30734283Rawat, A.; Vijaya Bhaskar Reddy, A. Recent advances on anticancer activity of coumarin derivatives. Eur. J. Med. Chem. Rep., 2022, 5, 100038. doi: 10.1016/j.ejmcr.2022.100038Insan, M.; Jaitak, V. New approaches to target cancer stem cells: Current scenario. Mini Rev. Med. Chem., 2014, 14(1), 20-34. doi: 10.2174/13895575113136660107 PMID: 24195662Matthews, H.K.; Bertoli, C.; de Bruin, R.A.M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol., 2022, 23(1), 74-88. doi: 10.1038/s41580-021-00404-3 PMID: 34508254Poorkiani, 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. doi: 10.4103/0971-5851.76190 PMID: 21584214Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin., 2023, 73(1), 17-48. doi: 10.3322/caac.21763 PMID: 36633525Cowin, P.; Rowlands, T.M.; Hatsell, S.J. Cadherins and catenins in breast cancer. Curr. Opin. Cell Biol., 2005, 17(5), 499-508. doi: 10.1016/j.ceb.2005.08.014 PMID: 16107313Sung, 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. doi: 10.3322/caac.21660 PMID: 33538338Emam, 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. doi: 10.1186/s13065-023-00995-2 PMID: 37501139Walker, 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. doi: 10.3399/bjgp14X682873 PMID: 25452544Tasmuth, 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. doi: 10.1093/oxfordjournals.annonc.a059215 PMID: 7669710Bish, 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. doi: 10.1016/j.jpsychores.2004.10.007 PMID: 15992567Wrensch, 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. doi: 10.1093/jnci/93.23.1791 PMID: 11734595Langford, 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. doi: 10.1016/j.jpainsymman.2014.11.292 PMID: 25527442Lee, 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. doi: 10.1007/s11136-017-1526-4 PMID: 28238091Katsura, C.; Ogunmwonyi, I.; Kankam, H.K.N.; Saha, S. Breast cancer: Presentation, investigation and management. Br. J. Hosp. Med., 2022, 83(2), 1-7. doi: 10.12968/hmed.2021.0459 PMID: 35243878Hamood, 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. doi: 10.1007/s10549-017-4485-0 PMID: 28861642Schou 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. doi: 10.1016/j.jpainsymman.2013.12.239 PMID: 24703940Weaver, D.L. Pathology evaluation of sentinel lymph nodes in breast cancer: Protocol recommendations and rationale. Mod. Pathol., 2010, 23(2), S26-S32. doi: 10.1038/modpathol.2010.36 PMID: 20436499Van 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. doi: 10.1023/A:1008287007819 PMID: 9862056Koo, 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. doi: 10.1016/j.canep.2017.04.010 PMID: 28549339Weigelt, 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. doi: 10.1038/nrclinonc.2009.166 PMID: 19942925Colditz, G.A. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J. Natl. Cancer Inst., 1998, 90(11), 814-823. doi: 10.1093/jnci/90.11.814 PMID: 9625169Clemons, M.; Goss, P. Estrogen and the risk of breast cancer. N. Engl. J. Med., 2001, 344(4), 276-285. doi: 10.1056/NEJM200101253440407 PMID: 11172156de 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. doi: 10.1021/acs.biochem.1c00806 PMID: 35238537Rouzier, 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. doi: 10.1158/1078-0432.CCR-04-2421 PMID: 16115903TilakVijay, J.; Vivek Babu, K.; Uma, A. Virtual screening of novel compounds as potential ERα; inhibitors. Bioinformation, 2019, 15(5), 321-332. doi: 10.6026/97320630015321 PMID: 31249434Tang, 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. doi: 10.3390/cells8101123 PMID: 31546660Hewitt, 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. doi: 10.1530/JME-15-0254 PMID: 26826253Das, 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. doi: 10.1016/j.molstruc.2022.133853Jaitak, 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. doi: 10.2174/0929867329666221006110528 PMID: 36201273Paterni, 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. doi: 10.1016/j.steroids.2014.06.012 PMID: 24971815Moon, 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. doi: 10.1038/s41418-019-0306-9 PMID: 30787391Rossouw, 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. doi: 10.1001/jama.288.3.321 PMID: 12117397Suliphuldevara 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. doi: 10.1002/slct.202204181Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89, 103021. doi: 10.1016/j.bioorg.2019.103021 PMID: 31176854Dorababu, A. Indole - a promising pharmacophore in recent antiviral drug discovery. RSC Med. Chem., 2020, 11(12), 1335-1353. doi: 10.1039/D0MD00288G PMID: 34095843Sidhu, 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. doi: 10.2174/1871520615666150520144217 PMID: 25991424Kaur, K.; Jaitak, V. Recent development in indole derivatives as anticancer agents for breast cancer. Anticancer. Agents Med. Chem., 2019, 19(8), 962-983. doi: 10.2174/1871520619666190312125602 PMID: 30864529Devi, 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. doi: 10.2174/1871520621999210104192644 PMID: 33397272Singla, 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. doi: 10.1016/j.ejmech.2018.01.051 PMID: 29407951Singla, 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. doi: 10.1016/j.bmc.2017.11.040 PMID: 29198894Singla, 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. doi: 10.1016/j.bioorg.2018.04.002 PMID: 29723744Jiang, 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. doi: 10.1016/j.ejmech.2021.113893 PMID: 34656899Laaroussi, 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. doi: 10.1016/j.ejmech.2020.112561 PMID: 32711231Shu, 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. doi: 10.1016/j.bmcl.2019.126925 PMID: 31901379Dadashpour, 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. doi: 10.1016/j.ejmech.2018.02.065 PMID: 29505935Komoto, 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. doi: 10.3390/ijms241310785 PMID: 37445965Mezgebe, 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. doi: 10.1021/acsomega.3c01035 PMID: 37305270Michalkova, 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. doi: 10.3390/pharmaceutics14030503 PMID: 35335879Robinson, 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. doi: 10.1021/jm201006x PMID: 22335538Cong, 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. doi: 10.1021/acs.molpharmaceut.8b00359 PMID: 30048137Badria, 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. doi: 10.3390/molecules24203728 PMID: 31623155Yan, 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. doi: 10.1021/acs.jmedchem.6b00021 PMID: 27149641Mayank; 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. doi: 10.1016/j.compbiolchem.2015.08.001 PMID: 26278973Berman, 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.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. doi: 10.1016/j.sjbs.2020.10.023 PMID: 33424323