Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
Bioorg Med Chem Lett. 2012 Jul 15;22(14):4859-63. doi: 10.1016/j.bmcl.2012.05.037. Epub 2012 May 23.
A structure-activity relationship study to elucidate the structural basis for hedgehog (Hh) signaling inhibition by vitamin D3 (VD3) was performed. Functional and non-functional regions of VD3 and VD2 were obtained through straightforward synthetic means and their biological activity was determined in a variety of cell-based assays. Several of these compounds inhibited Hh signaling at levels comparable to the parent VD3 with no effects on canonical vitamin D signaling. Most notably, compounds 5 and 9, demonstrated potent inhibition of the Hh pathway, exhibited no binding affinity for the vitamin D receptor (VDR), and did not activate VDR in cell culture. In addition, several compounds exhibited anti-proliferative activity against two human cancer cell lines through a mechanism distinct from the Hh or VDR pathways, suggesting a new cellular mechanism of action for this class of compounds.
进行了一项结构-活性关系研究，以阐明维生素 D3（VD3）抑制刺猬（Hh）信号的结构基础。通过直接的合成手段获得了 VD3 和 VD2 的功能和非功能区域，并在各种基于细胞的测定中测定了它们的生物活性。这些化合物中的几种在与母体 VD3 相当的水平上抑制了 Hh 信号，对经典维生素 D 信号没有影响。值得注意的是，化合物 5 和 9 对 Hh 途径表现出强烈的抑制作用，对维生素 D 受体（VDR）没有结合亲和力，并且在细胞培养中不会激活 VDR。此外，几种化合物通过与 Hh 或 VDR 途径不同的机制对两种人癌细胞系表现出抗增殖活性，这表明该类化合物具有新的细胞作用机制。
