Banerjee Upasana, DeBerardinis Albert M, Hadden M Kyle
Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA.
Bioorg Med Chem. 2015 Feb 1;23(3):548-55. doi: 10.1016/j.bmc.2014.12.005. Epub 2014 Dec 10.
Vitamin D3 (VD3) is a moderately potent and non-selective inhibitor of the Hedgehog (Hh) signaling cascade. Previous studies have established that the CD-ring region of VD3 serves as the Hh inhibitory pharmacophore. Subsequently, compound 3, an ester linked aromatic A-ring and CD-ring derivative was identified as an improved and selective Hh inhibitor. Herein, we report modifications of the CD-ring side chain that afford enhancement of selectivity for Hh modulation thereby diminishing the detrimental effects of concomitant vitamin D receptor activation. In general, linear or moderately branched alkyl chains of five or six carbons were optimal for potent and selective inhibition of Hh signaling. Moreover, hybrid VD3 side chain derivative 20 demonstrated 4-fold improvement in Hh antagonistic activity over VD3(IC50=1.1-1.6 μM) while gaining greater than a 1000-fold selectivity for Hh signaling over canonical activation of the vitamin D receptor pathway.
维生素D3（VD3）是一种中等强度的非选择性刺猬信号通路（Hh）抑制剂。先前的研究表明，VD3的C-D环区域是Hh抑制药效基团。随后，化合物3，一种酯连接的芳香A环和C-D环衍生物，被鉴定为一种改进的选择性Hh抑制剂。在此，我们报道了C-D环侧链的修饰，这种修饰提高了对Hh调节的选择性，从而减少了伴随的维生素D受体激活的有害影响。一般来说，五或六个碳的直链或适度支化的烷基链对于有效和选择性抑制Hh信号是最佳的。此外，杂合VD3侧链衍生物20在Hh拮抗活性方面比VD3提高了4倍（IC50=1.1-1.6μM），同时在Hh信号传导方面比维生素D受体途径的经典激活具有超过1000倍的选择性。
