Syntheses of Antileishmanial Sterols and Structural Analogues from Pentalinon andrieuxii

Leishmaniasis is a neglected, parasitic disease transmitted through the bite of infected sandflies. In an effort to identify novel compounds demonstrating activity against the parasite, a multidisciplinary research effort involving natural product isolation, chemical synthesis, and biological evaluation was initiated. Recently, our group reported the isolation of several sterols from the roots of Pentalinon andrieuxii, a plant native to Mexico, that show potent antileishmanial activity both in vitro and in vivo. Analysis of these compounds indicated three distinct structural subtypes and afforded preliminary structure-activity relationship (SAR) data. Semi-synthetic approaches toward these structural classes from readily available, commercial starting materials have been carried out to prepare the molecules in quantities sufficient to enable detailed mechanistic studies and SAR studies. Syntheses of pentalinonsterol and ergosta-4,24(28)-dien-3-one, members of the first two classes, respectively, have already been accomplished and the synthesis of an advanced intermediate of 6,7-dihydroneridienone, the compound displaying the most potent antileishmanial activity and a representative member of the third class possessing, has also been achieved. These synthetic efforts have also facilitated the preparation of a number of structurally related analogues and probes designed to explore the mechanism of action of this class of natural product.