Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

7-O-Tyrosyl Silybin Derivatives as a Novel Set of Anti-prostate Cancer Compounds

Valeria Romanucci
ORCID logo ,
Rita Pagano
ORCID logo ,
Kushal Kandhari
ORCID logo ,
Armando Zarrelli
,
Maria Petrone
,
Chapla Agarwal
,
Rajesh Agarwal
,
Giovanni Di Fabio
* ORCID logo
Version 1 : Received: 28 February 2024 / Approved: 28 February 2024 / Online: 29 February 2024 (08:22:17 CET)

A peer-reviewed article of this Preprint also exists.

Romanucci, V.; Pagano, R.; Kandhari, K.; Zarrelli, A.; Petrone, M.; Agarwal, C.; Agarwal, R.; Di Fabio, G. 7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds. Antioxidants 2024, 13, 418. Romanucci, V.; Pagano, R.; Kandhari, K.; Zarrelli, A.; Petrone, M.; Agarwal, C.; Agarwal, R.; Di Fabio, G. 7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds. Antioxidants 2024, 13, 418.

Abstract

Silybin is a natural compound extensively studied for its hepatoprotective, neuroprotective and anti-cancer properties. Envisioning the enhancement of silybin potential by suitable modifications in its chemical structure, here, a series of new 7-O alkyl silybins derivatives were synthesized by Mitsunobu reaction starting from the silybins and tyrosol-based phenols, such as tyrosol (TYR, 3), 3-methoxytyrosol (MTYR, 4) and 3-hydroxytyrosol (HTYR, 5). This research sought to explore the antioxidant and anticancer properties of new eighteen derivatives and their mechanisms. In particular, the antioxidant properties of new derivatives outlined by DPPH assay, showed a very pronounced activity depending on the tyrosyl moiety (HTYR>MTYR>>TYR). A significant contribution of the HTYR moiety was observed for silybins and 2,3-dehydro-silybin based derivatives. According to the very potent antioxidant activity, 2,3-dehydro-silybin derivatives 15ab, 15a and 15b exerted the most potent anticancer activity in human prostate cancer PC-3 cells. Furthermore, flow cytometric analysis for cell cycle and apoptosis revealed that 15ab, 15a and 15b induce strong G1 phase arrest and increase late apoptotic population in PC-3 cells. Additionally, western blotting for apoptotic marker cleaved caspase-3 confirmed apoptosis induction by these silybin derivatives in PC-3 cells. These findings hold significant importance in the investigation of anticancer properties of silybin derivatives and strongly encourage swift investigation in pre-clinical models and clinical trials.

Keywords

Silibinin; Silybin; Natural products; Mitsunobu reaction; Antioxidants; Human prostate cancer

Subject

Chemistry and Materials Science, Organic Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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