3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation

To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaff...

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Autores principales:	Sitong Wu, Guanglin Chen, Qiang Zhang, Guangdi Wang, Qiao-Hong Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	silibinin carbamoylation prostate cancer cell proliferation androgen receptor Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/e523de46002940f9b5086286570ef89c
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spelling	oai:doaj.org-article:e523de46002940f9b5086286570ef89c2021-11-11T18:26:20Z3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation10.3390/molecules262164211420-3049https://doaj.org/article/e523de46002940f9b5086286570ef89c2021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6421https://doaj.org/toc/1420-3049To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure–activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2–C3, providing an avenue for achieving 3-<i>O</i>-carbamoyl-5,7,20-<i>O</i>-trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3-<i>O</i>-carbamoyl-3′,4′,5,7-<i>O</i>-tetramethyltaxifolins. The antiproliferative potency of 5,7,20-<i>O</i>-trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an AR-positive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20-<i>O</i>-trimethylsilybin and four 3-<i>O</i>-carbamoyl-5,7,20-<i>O</i>-trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC<sub>50</sub> values of these five 5,7,20-<i>O</i>-trimethylsilybins against the LNCaP cells fall into the range of 0.11–0.83 µM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20-<i>O</i>-trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer.Sitong WuGuanglin ChenQiang ZhangGuangdi WangQiao-Hong ChenMDPI AGarticlesilibinincarbamoylationprostate cancercell proliferationandrogen receptorOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6421, p 6421 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	silibinin carbamoylation prostate cancer cell proliferation androgen receptor Organic chemistry QD241-441
spellingShingle	silibinin carbamoylation prostate cancer cell proliferation androgen receptor Organic chemistry QD241-441 Sitong Wu Guanglin Chen Qiang Zhang Guangdi Wang Qiao-Hong Chen 3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
description	To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure–activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2–C3, providing an avenue for achieving 3-<i>O</i>-carbamoyl-5,7,20-<i>O</i>-trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3-<i>O</i>-carbamoyl-3′,4′,5,7-<i>O</i>-tetramethyltaxifolins. The antiproliferative potency of 5,7,20-<i>O</i>-trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an AR-positive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20-<i>O</i>-trimethylsilybin and four 3-<i>O</i>-carbamoyl-5,7,20-<i>O</i>-trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC<sub>50</sub> values of these five 5,7,20-<i>O</i>-trimethylsilybins against the LNCaP cells fall into the range of 0.11–0.83 µM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20-<i>O</i>-trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer.
format	article
author	Sitong Wu Guanglin Chen Qiang Zhang Guangdi Wang Qiao-Hong Chen
author_facet	Sitong Wu Guanglin Chen Qiang Zhang Guangdi Wang Qiao-Hong Chen
author_sort	Sitong Wu
title	3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
title_short	3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
title_full	3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
title_fullStr	3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
title_full_unstemmed	3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation
title_sort	3-<i>o</i>-carbamoyl-5,7,20-<i>o</i>-trimethylsilybins: synthesis and preliminary antiproliferative evaluation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e523de46002940f9b5086286570ef89c
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3-<i>O</i>-Carbamoyl-5,7,20-<i>O</i>-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation

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