Synthesis and Evaluation of Osteogenic Oxysterols as Hedgehog Pathway Activators

Abstract

Oxysterols (OHCs) are metabolic byproducts of cholesterol that are known to function as agonists of the Hedgehog (Hh) signaling pathway. Previously, we reported 23(S)-hydroxycholesterol [23(S)-OHC, 4] as a potent activator of Hh signaling with the ability to functionally differentiate mouse embryonic fibroblasts to an osteogenic fate. To obtain 23(S)-OHC in quantities suitable for in vivo evaluation, we developed a revised synthetic route that decreases the number of steps and chromatographic purifications, and which also enhances the stereoselective nature of the synthesis. This new route also allows access to the C21 methyl group of the OHC scaffold, and several new analogues with varying stereochemistry at this location were evaluated for their ability to up-regulate the Hh pathway.

Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization

“…Oxy234 is a 20(R)secondary alcohol, expectedly displaying an extended side-chain conformation. Accordingly, both Oxy43 and Oxy234 are devoid of significant Hh pathway inhibitory properties and display weak Hh pathway stimulation instead (unpublished observations) [68]. We found that Oxy43 and Oxy234 both possess significant anti-inflammatory properties, with Oxy43′s effects being similar to and Oxy234′s effects slightly weaker compared to Oxy210 (Figure 6).…”