Design, Synthesis and Biological Evaluation of Aromatase Inhibitors Based on Sulfonates and Sulfonamides of Resveratrol.

Marialuigia Fantacuzzi,Alessandra Ammazzalorso,Marialucia Gallorini,Simone Carradori,Marwa Balaha,Zeineb Aturki,Barbara De Filippis,Orazio Nicolotti,Amelia Cataldi,Letizia Giampietro,Rosa Amoroso,Cristina Maccallini,Nicola Gambacorta

doi:10.3390/ph14100984

Abstract

A library of sulfonate and sulfonamide derivatives of Resveratrol was synthesized and tested for its aromatase inhibitory potential. Interestingly, sulfonate derivatives were found to be more active than sulfonamide bioisosteres with IC50 values in the low micromolar range. The sulfonate analogues 1b–c and 1j exhibited good in vitro antiproliferative activity on the MCF7 cell line, evidenced by MTT and LDH release assays. Structure–activity relationships suggested that electronic and lipophilic properties could have a different role in promoting the biological response for sulfonates and sulfonamides, respectively. Docking studies disclosed the main interactions at a molecular level of detail behind the observed inhibition of the more active compounds whose chemical stability has been evaluated with nano-liquid chromatography. Finally, 1b–c and 1j were highlighted as sulfonates to be further developed as novel and original aromatase inhibitors.

Highlights

Breast cancer is one of the leading causes of cancer-related deaths in women
In the past few years, we focused on the synthesis of various series of RSV derivatives
The synthesis of compounds 1a–k and 2a–k was made by the reaction of the proper commercial 4-hydroxystilbene or 4-aminostilbene and the commercial aryl or alkylsulfonylchloride, in the presence of triethylamine in dry DMF for sulfonates, or dry DCM for sulfonamides, at 0 ◦ C and in an anhydrous atmosphere

Summary

Introduction

Breast cancer is one of the leading causes of cancer-related deaths in women. It is treated principally by surgical methods, radiotherapy, and endocrine therapies [1]. A member of the cytochrome P450 family (CYP19), is responsible for a key step of the biosynthesis of estrogens. It has been broadly reported that high levels of estrogens stimulate the hormone-dependent breast cancer (HDBC) and metastasis in both pre- and post-menopausal woman [2]. A reduction in estrogen levels by aromatase inhibition is crucial for the management of hormone-sensitive breast cancer. Under some situations (e.g., post-menopause), aromatase has a key role in estrogen production, and inhibitors have been shown to function as chemo-preventive

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Results

Conclusion