Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

A New Class of Pure Estrogen Alpha Receptor Antagonists; Design, Synthesis and in-vitro Screening

Author(s): Akbar John Jameera Begam, Katike Ahamed Basheer, Selvaraj Jubie*, Srikanth Jupudi, Mohammed Afzal Azam and Palanisamy Dhanabal

Volume 16, Issue 1, 2019

Page: [66 - 81] Pages: 16

DOI: 10.2174/1570180815666180327124634

Price: $65

Abstract

Background: In view of the estrogenic receptor inhibitory properties of coumarin nucleus, long chain nature of fatty acid and anti-breast cancer activity of fatty acids, it was proposed to attach long chain fatty acids at 3rd,4th and 7th position of coumarin nucleus and evaluate for their anti-breast cancer activity through suitable in-vitro methods.

Methods: The present study focuses a library of fatty acid coumarin conjugates as ligands to the ligand-binding domain of the human estrogen receptor α (PDB ID 2IOG) and their binding affinities using GLIDE module of Schrodinger after ascertaining their drug-likeness with QIKPROP. The compounds LNAC 8, SAC 1 and OAC 5 are the best hits based on their docking scores as well as the Prime MM-GBSA free energy of binding. Based on the in-silico results and synthetic feasibility the compounds SAC 1 PAC 1 and OAC 1 are synthesized, characterized and investigated for their time interval growth inhibitory effect on MCF-7 which is an ER positive breast cancer cell lines.

Results: SAC 1, showed better in vitro growth inhibitory effect in sub micromolar range as compared to Tamoxifen, a standard estrogen receptor modulator.

Conclusion: Conclusively, in silico molecular docking studies have been very useful in predicting the pharmacokinetic profiles and the binding affinities of new hits before a detailed preclinical and clinical evaluation.

Keywords: Estrogen receptor, coumarin, fatty acids, cytotoxicity, GLIDE, MMGBSA.

Graphical Abstract
[1]
Canez, M.S.; Lee, K.J.; Olive, D.L. Progestogens and estrogens. Infertil. Reprod. Med. Clin. North Am, 1992, 3(59), 59-77.
[2]
Peter, V.; Barbara, O.; Simona, M.B.; Janja, M. The many faces of estrogen signaling. Biochem. Med., 2014, 24(3), 329-342.
[3]
John, S.C.; Jesse, E.; Musiliyu, M.; Devora, S.; Abdul, D.M.; Kwon, K.P.; Zhongliang, W. Synthesis and evaluation of estradiol derivatives as anti-breast cancer agent. Lett. Drug Des. Discov., 2010, 7(6), 389-394.
[4]
Prasanna, G.A.; Corey, S.; Arul, M.C. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res., 2014, 16, 494.
[5]
Lars, A.H.; Chunyan, Z.; Karin, D.W. Estrogen receptor beta in breast cancer. Mol. Cell. Endocrinol., 2014, 382(1), 665-672.
[6]
Sudipa, S.R.; Ratna, K.V. Role of estrogen receptor signaling in breast cancer metastasis. Int. J. Breast Cancer, 2012, 2012, 654698.
[7]
Matthews, S.B.; Sartorius, C.A. Steroid hormone receptor positive breast cancer patient-derived xenografts. Horm. Cancer, 2017, 8(1), 4-15.
[8]
Chapman, K.B.; Prendes, M.J.; Kidd, J.L.; Sternberg, H.; West, M.D.; Wagner, J. Elevated expression of cancer/testis antigen FSIP1 in ER-positive breast tumors. Biomarkers Med., 2013, 7(4), 601-611.
[9]
Faizeh, A.; Stacy, A.M.; Seid, M.; Agnes, D.; Marti, J.; Rasha, H. Estrogen receptor-dependent genomic expression profile in breast cancer cells in response to fatty acids. J. Carcinog., 2009, 8, 17.
[10]
Disha, J.; John, T.K. A mutant-selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements. Bioorg. Med. Chem. Lett., 2010, 20(17), 5258-5261.
[11]
Susannah, J.S.; Atul, P.; Lawrence, W.; Saulat, S.; David, V.; Rebecca, W.; Richard, H.; Wilson, Z.; Michael, J.; Charles, C.R. Phase I study of STX 64 (667 Coumate) in breast cancer patients: The first study of a steroid sulfatase inhibitor. Clin. Cancer Res., 2006, 12(5), 1585-1592.
[12]
Musiliyu, A.M.; John, S.C.; Omar, F.K. A review of coumarin derivatives in pharmacotherapy of breast cancer. Curr. Med. Chem., 2008, 15(26), 2664-2679.
[13]
Salimon, J.; Salih, N.; Yousif, E. Industrial development and applications of plant oils and their bio based oleochemicals. Arab. J. Chem., 2012, 5, 135-145.
[14]
Carol, J.F.; Bruce, F.; Stephen, D.H. Omega3fatty acids for breast cancer prevention and survivorship. Breast Cancer Res., 2015, 17, 62.
[15]
Schrodinger, L.L.C. New York, USA: Schrodinger Inc.; 2008. Available from: http://www.schrodinger.com
[16]
Shivakumar, D.; Williams, J.; Wu, Y.; Damm, W.; Shelley, J.; Sherman, W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J. Chem. Theory Comput., 2010, 6, 1509-1519.
[17]
Li, J.; Abel, R.; Zhu, K.; Cao, Y.; Zhao, S.; Friesner, R.A. The VSGB 2.0 Model: A next generation energy model for high resolution protein structure modeling. Proteins, 2011, 79, 2794-2812.
[18]
Fadia, H.; Mohammad, K.; Khaled, A.; Joumaa, M.; Ayman, K. Synthesis and nitration of 7-hydroxy-4-methyl coumarin via pechmann condensation using eco-friendly medias. Int. Lett. Chem. Phys., 2016, 69, 66-73.
[19]
Bauer, S.T. The preparation of fatty acid chlorides. Oil Soap, 1946, 23, 1-5.
[20]
Terry, L.R.; Richard, A.M.; Andrew, L.N.; Sarah, D. Cell Viability Assays. Assay Guidance Manual, Available on: https://www.ncbi. nlm.nih.gov/books/NBK144065/
[21]
Suganya, J.; Radha, M.; Devi, L.N.; Nishandhini, M. In silico docking studies of selected flavonoids - natural healing agents against breast cancer. Asian Pac. J. Cancer Prev., 2014, 15(19), 8155-8159.
[22]
Etti, I.; Abdullah, R.; Hashim, N.M.; Kadir, A.; Abdul, A.B.; Etti, C.; Malami, I.; Waziri, P.; How, C.W. Artonin E and structural analogs from artocarpus species abrogates estrogen receptor signaling in breast cancer. Molecules, 2016, 21(839), 1-17.
[23]
Perdih, A.; Bren, U.; Solmajer, T.J. Binding free energy calculations of N-sulphonyl-glutamic acid inhibitors of MurD ligase. J. Mol. Model., 2009, 15, 983-996.
[24]
Desai, N.; Mahto, M.K.; Alekhya, B.; Naveen, C.R.; Bhaskar, P.M. Comparative docking studies of estrogen receptor inhibitors and their binding interaction analysis. Int. J. Pharm. Sci. Rev. Res., 2012, 16, 91-95.

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