Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06029-3092, USA.
ChemMedChem. 2018 Apr 6;13(7):748-753. doi: 10.1002/cmdc.201700792. Epub 2018 Feb 27.
The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small-molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the "northern region" of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C4 hydroxy group and C3α proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 ((1R,3aR,4R,7aR)-1-[(R)-1,5-dimethylhexyl]-4-(4-aminophenoxy)-7a-methyloctahydro-1H-indene) demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway.
刺猬（Hh）信号通路对于胚胎模式形成和胚胎后组织再生至关重要。通路的组成性激活也与人类恶性肿瘤有关，如基底细胞癌（BCC）和髓母细胞瘤；因此，正在开发多种抑制 Hh 信号的小分子支架。先前，Grundmann 醇，也称为维生素 D3（VD3）的“北方区域”，已被确定为中度 Hh 途径抑制剂。在这项研究中，研究了具有不同 C4 羟基和 C3α 质子取向的 Grundmann 醇异构体，以确定对于这种六氢茚烷支架而言，关于 Hh 抑制的最佳构型。通过醚或硫醚接头将 Grundmann 醇连接到取代的苯基或苄基环的一系列类似物被合成并评估了它们的抗 Hh 活性。其中，类似物 17（（1R，3aR，4R，7aR）-1-（（R）-1,5-二甲基己基）-4-（4-氨基苯氧基）-7a-甲基八氢-1H-茚）在 Hh 依赖性 BCC 细胞中表现出强烈的抗 Hh 活性，并且不会激活典型的维生素 D 受体信号传导，表明其对 Hh 信号通路具有选择性。
