Synthesis of sterols with antileishmanial activity from Pentalinon andrieuxii

Abstract

Leishmaniasis is a parasitic disease transmitted through the bite of infected sandflies. Although therapeutics are currently available for the treatment of the disease, the emergence of drug resistance in the parasites suggests a continued need for the discovery of novel chemical entities that act via new or different mechanisms of action. In an effort to identify compounds which may be effective for the treatment of leishmaniasis, a multidisciplinary research effort involving natural product isolation, chemical synthesis, and biological evaluation was initiated. Several sterols were isolated from the roots of Pentalinon andrieuxii, a plant native to Mexico, that show potent antileishmanial activity both in vitro and in vivo. A structural survey of the active compounds indicated three distinct structural subtypes. Semi-synthetic approaches toward these structural classes from affordable, commercially available starting materials have been designed to prepare the molecules in quantities sufficient to enable detailed mechanistic studies and structure-activity relationship studies. Representative examples from two of the classes, pentalinonsterol and ergosta-4,24(28)-dien-3-one, have been synthesized from 5-pregnen-3β-ol-20-one and lithocholic acid, respectively. These routes have also facilitated the preparation of a number of structurally related analogues.