Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
J Med Chem. 2014 May 8;57(9):3724-36. doi: 10.1021/jm401812d. Epub 2014 Apr 28.
A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
对一系列基于维生素 D3（VD3）的类似物进行了结构-活性关系研究，这些类似物包含具有不同功能的芳香 A 环模拟物，为导致强效、选择性 Hedgehog（Hh）途径抑制的支架特征提供了重要见解。包含（1）芳香 A 环的邻位或对位的单取代、（2）杂芳基或联芳基部分、或（3）芳香 A 环上的多个取代基的三种类似物亚类被制备并进行了评估。在六元环上包含单取代或多个亲水基团的芳香 A 环模拟物在 Hh 依赖性小鼠胚胎成纤维细胞和培养的癌细胞中均抑制 Hh 途径（IC50 值为 0.74-10 μM）。进行了初步研究以探究 VD3 和最活跃的类似物 5 抑制 Hh 信号转导的细胞机制。这些研究表明，VD3 的抗 Hh 活性主要归因于维生素 D 受体，而 5 通过单独的机制影响 Hh 抑制。
