Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors

Abstract

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.

Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties

“…To continue our SAR exploration of this region of the scaffold, we sought to synthesize and evaluate analogues that continue the scaffold truncation that we previously probed by removing the phenyl ring on the “right side” of the scaffold and directly appending the 3-phenolic carboxylic acid of 2 to the piperazine amine to provide analogue 3 . We evaluated this analogue for its ability to decrease Gli1 mRNA expression in the Hh-dependent murine BCC cell line ASZ001. − Analogue 3 demonstrated comparable anti-Hh activity compared to 2 (IC 50 values = 0.26 μM and 0.16 μM, respectively), verifying that this series of compounds retains potent Hh inhibition and encouraging us to synthesize additional analogues that incorporate the 4-phenylpiperazinyl amide.…”

Design of Hedgehog pathway inhibitors for cancer treatment

“…To gain in-depth understanding of GA’s alcohol and its analogues as Hh inhibitors, Wen et al 106 recently reported the synthesis and Hh inhibitory potential of GA linked to a substituted phenyl or benzyl ring via an ether or thioether linker. For phenyl-substituted GA isomers and corresponding ether-linked 4-aniline analogues demonstrated potent anti-Hh activity in C3H10T1/2 cells, whereas precursor 4-nitro derivatives were inactive.…”

PTML Model of ChEMBL Compounds Assays for Vitamin Derivatives

“…The organic synthesis of analogs of vitamins is an active field of interest for medicinal chemistry, pharmaceuticals, and the food additive industry . For instance, vitamin D 3 analogs synthesis has been promoted given its capacity to modulate signaling pathways with the objective of discover desirable effects in cancer cells. − We can consider other examples, such as vitamin K analogs, used as possible cancer therapies because of the inhibition produced in the growth of cancer cells by mechanisms, such as apoptosis, cell cycle arrest, and autophagy . In addition, their characteristics may be used to develop stem-cell-based therapies for neurodegenerative diseases .…”