Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Letter Article

Novel Carbamοyloxy Analogues of Tamoxifen: Synthesis, Molecular Docking and Bioactivity Evaluation

Author(s): Konstantinos M. Kasiotis*, George Lambrinidis, Nikolas Fokialakis and Serkos A. Haroutounian

Volume 18, Issue 5, 2021

Published on: 04 November, 2020

Page: [422 - 428] Pages: 7

DOI: 10.2174/1570180817999201104125630

Price: $65

Abstract

Background: Tamoxifen (TAM), a non-steroidal antiestrogen, constitutes the endocrine treatment of choice against breast cancer. Since its inauguration, substantial effort has been devoted towards the design and synthesis of TAM’s analogues aiming to improve its bioactivity and reveal their structure-activity relationship.

Objective: One of the most studied synthetic features of TAM’s structure is the ether side chain, which is strongly related to its positioning into the active site of the Estrogen Receptors (ERα and ERβ). Herein, we present the application of a straightforward route for the efficient synthesis of selected novel carbamoyloxy analogues of TAM and the evaluation of their respective binding affinities to the Estrogen Receptors α and β.

Methods: A one-pot reaction was applied for the construction of TAM’s triarylethylene core moiety, which subsequently was derivatized to provide efficiently the target carbamoyloxy analogues of TAM. The Z and E isomers of the latter were separated using RP-HPLC-UV and their binding affinities to ERα and ERβ were measured.

Results: Among all compounds synthesized, the dimethyl derivative was determined as the most potent for both receptors, displaying binding affinity values comparable to TAM, though the Zdiethyl analogue maintained substantial affinity to both ERs. The aforementioned results were further studied by theoretical calculations and molecular modelling to delineate a concordance among calculations and biological activity.

Conclusion: Approach applied herein permitted the extraction of a useful structure-activity relationship correlation pattern highlighting the importance of a chemically stabilized tamoxifen side chain.

Keywords: Tamoxifen, triarylethylene, breast cancer, estrogen receptor, binding affinity, TAM.

« Previous Next »
Graphical Abstract

[1]
Maximov, P.Y.; McDaniel, R.E.; Jordan, V.C. Tamoxifen: Pioneering Medicine in Breast Cancer; Springer: Basel, 2013.
[http://dx.doi.org/10.1007/978-3-0348-0664-0]
[2]
Harper, M.J.; Walpole, A.L. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature, 1966, 212(5057), 87.
[http://dx.doi.org/10.1038/212087a0] [PMID: 5965580]
[3]
Bedford, G.R.; Richardson, D.N. Preparation and Identification of cis and trans isomers of a substituted triarylethylene. Nature, 1966, 212, 733-734.
[http://dx.doi.org/10.1038/212733b0]
[4]
Group, E.B.C.T.C. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet, 1998, 351(9114), 1451-1467.
[http://dx.doi.org/10.1016/S0140-6736(97)11423-4] [PMID: 9605801]
[5]
Jordan, V.C. Tamoxifen: a most unlikely pioneering medicine. Nat. Rev. Drug Discov., 2003, 2(3), 205-213.
[http://dx.doi.org/10.1038/nrd1031] [PMID: 12612646]
[6]
Barkhem, T.; Carlsson, B.; Nilsson, Y.; Enmark, E.; Gustafsson, J.; Nilsson, S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol., 1998, 54(1), 105-112.
[http://dx.doi.org/10.1124/mol.54.1.105] [PMID: 9658195]
[7]
Weinberg, O.K.; Marquez-Garban, D.C.; Pietras, R.J. New approaches to reverse resistance to hormonal therapy in human breast cancer. Drug Resist. Updat., 2005, 8(4), 219-233.
[http://dx.doi.org/10.1016/j.drup.2005.06.002] [PMID: 16054421]
[8]
Lumachi, F.; Luisetto, G.; Basso, S.M.; Basso, U.; Brunello, A.; Camozzi, V. Endocrine therapy of breast cancer. Curr. Med. Chem., 2011, 18(4), 513-522.
[http://dx.doi.org/10.2174/092986711794480177] [PMID: 21143113]
[9]
El Sayed, R.; El Jamal, L.; El Iskandarani, S.; Kort, J.; Abdel Salam, M.; Assi, H. Endocrine and targeted therapy for hormone-receptor-positive, her2-negative advanced breast cancer: Insights to sequencing treatment and overcoming resistance based on clinical trials. Front. Oncol., 2019, 9, 510.
[http://dx.doi.org/10.3389/fonc.2019.00510] [PMID: 31281796]
[10]
Guo, W.Y.; Zeng, S.M.Z.; Deora, G.S.; Li, Q.S.; Ruan, B.F. Estrogen Receptor α (ER α)-targeting compounds and derivatives: Recent advances in structural modification and bioactivity. Curr. Top. Med. Chem., 2019, 19(15), 1318-1337.
[http://dx.doi.org/10.2174/1568026619666190619142504] [PMID: 31215379]
[11]
Elghazawy, N.H.; Engel, M.; Hartmann, R.W.; Hamed, M.M.; Ahmed, N.S.; Abadi, A.H. Design and synthesis of novel flexible ester-containing analogs of tamoxifen and their evaluation as anticancer agents. Future Med. Chem., 2016, 8(3), 249-256.
[http://dx.doi.org/10.4155/fmc.15.181] [PMID: 26898104]
[12]
Ahmed, N.S.; Wober, J. Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF-7 cell line. Drug Dev. Res., 2020, 81(4), 444-455.
[http://dx.doi.org/10.1002/ddr.21637] [PMID: 31916635]
[13]
Ahmed, N.S.; Elghazawy, N.H.; ElHady, A.K.; Engel, M.; Hartmann, R.W.; Abadi, A.H. Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism. Eur. J. Med. Chem., 2016, 112, 171-179.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.026] [PMID: 26896706]
[14]
Wang, Q.; Yang, X.; Wu, P.; Yu, Z. Photoredox-catalyzed C-H arylation of internal alkenes to tetrasubstituted alkenes: Synthesis of tamoxifen. Org. Lett., 2017, 19(22), 6248-6251.
[http://dx.doi.org/10.1021/acs.orglett.7b03223] [PMID: 29095630]
[15]
Schneider, M.R.; Schuderer, M.L. 1-[4-(N,N-bis-beta-chloroethylcarbamoyloxy)-phenyl]-1,2-bis- (hydroxyphenyl)-but-1-enes: drugs specifically targeted against estrogen receptor positive mammary tumors. Arch. Pharm. (Weinheim), 1990, 323(4), 215-219.
[http://dx.doi.org/10.1002/ardp.19903230407] [PMID: 2360864]
[16]
Kasiotis, K.M.; Lambrinidis, G.; Fokialakis, N.; Tzanetou, E.N.; Mikros, E.; Haroutounian, S.A. Novel carbonyl analogs of tamoxifen: Design, synthesis, and biological evaluation. Front Chem., 2017, 5, 71.
[http://dx.doi.org/10.3389/fchem.2017.00071] [PMID: 29018796]
[17]
Manns, J.E.; Hanks, S.; Brown, J.E. Optimised separation of E- and Z- isomers of tamoxifen, and its principal metabolites using reversed-phase high performance liquid chromatography. J. Pharm. Biomed. Anal., 1998, 16(5), 847-852.
[http://dx.doi.org/10.1016/S0731-7085(97)00116-7] [PMID: 9535197]
[18]
Jager, N.G.L.; Rosing, H.; Linn, S.C.; Schellens, J.H.M.; Beijnen, J.H. Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: Focus on endoxifen and 4-hydroxytamoxifen. Breast Cancer Res. Treat., 2012, 133(2), 793-798.
[http://dx.doi.org/10.1007/s10549-012-2000-1] [PMID: 22388692]

Rights & Permissions Print Cite
Article Metrics
23
1
© 2024 Bentham Science Publishers | Privacy Policy