Synthesis and Evaluation of Aromatic A-Ring 23-Oxavitamin D Analogues As Hedgehog Pathway Inhibitors

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Feb 26

PMID 40004093

Authors

Wang Chen

Feifan Lai

Jianghe Xu

Affiliations

Soon will be listed here.

Abstract

The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D (VD) and its derivatives have been identified as potent Hh inhibitors. However, the selectivity of VD derivatives to vitamin D receptor (VDR) and the Hh signaling pathway still needs optimization. In this study, a series of aromatic A-ring mimics VD analogues that contain a C-23 oxygen atom or incorporate C-25 hydroxyl on side chains were designed and synthesized. These compounds were tested in various cell lines for anti-Hh activity, with analogues and identified as potent inhibitors. Mechanism studies showed their anti-Hh effects are mainly due to targeting Smoothened (Smo) without binding to the cyclopamine site. Structure-activity relationship (SAR) studies revealed that VD-based inhibitors enhance anti-Hh activity by adding a hydroxyl group at C25 while reducing VDR activity by incorporating an oxygen atom into the side chain.

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