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Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors
Author(s) -
Wen Jiachen,
Hadden M. Kyle
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700792
Subject(s) - hedgehog signaling pathway , stereochemistry , chemistry , hedgehog , linker , signal transduction , biochemistry , computer science , operating system
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 ((1 R ,3a R ,4 R ,7a R )‐1‐[( R )‐1,5‐dimethylhexyl]‐4‐(4‐aminophenoxy)‐7a‐methyloctahydro‐1 H ‐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.