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Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

Kandil, Sahar B. ORCID: https://orcid.org/0000-0003-1806-9623, Kariuki, Benson M. ORCID: https://orcid.org/0000-0002-8658-3897, McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X and Westwell, Andrew D. ORCID: https://orcid.org/0000-0002-5166-9236 2021. Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer. Bioorganic and Medicinal Chemistry Letters 36 , 127817. 10.1016/j.bmcl.2021.127817

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Abstract

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 µM) and enzalutamide (IC50 = 11.47 – 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Pharmacy
Publisher: Elsevier
ISSN: 0960-894X
Date of First Compliant Deposit: 8 February 2021
Date of Acceptance: 19 January 2021
Last Modified: 24 Nov 2022 00:14
URI: https://orca.cardiff.ac.uk/id/eprint/138350

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