Synthesis of obtusifoliol and analogues as CYP51 substrates

Sterol 14 alpha-demethylases (CYP51s) are a ubiquitous superfamily of cytochrome P450 enzymes that play an essential role in sterol biosynthesis. As fungal CYP51s are the target of azole-based antifungal agents, which are facing the problem of increasing resistance, the substrate specificity of this enzyme subclass has recently garnered significant attention. Herein we report the first chemical synthesis of the final endogenous substrate of this enzyme class, obtusifoliol, in 1.3% yield across ten steps from a commercially available lanosterol mixture. Intermediates along this pathway provide a basis for further derivatisation of the sterol skeleton and future investigation into CYP51 inhibition to overcome pathogens' azole resistance.

Automated summary

This study reports the first chemical synthesis of the final endogenous substrate of the sterol 14 alpha-demethylases (CYP51s), obtusifoliol, and demonstrates the potential for further investigation into the derivatisation of the sterol skeleton and the development of CYP51 inhibitors to overcome azole resistance in antifungal agents.