Route Optimization and Derivatization of the Antileishmanial Pentalinonsterol

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The Ohio State University

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Leishmaniasis is a vector born disease identified by WHO as a globally neglected health problem. With 310 million people living at risk, there are an estimated 1.3 million new cases and 30-40 thousand deaths occurring annually. Current chemotherapeutics are limited by toxicity, cost, deliverability, patient compliance, and emergence of resistance. In an attempt to discover novel antileishmanials, the Kinghorn group isolated several biologically active compounds from the hexane extracts of the roots of Pentalinon andrieuxii. The roots have historically been used to alleviate skin ulcers formed by cutaneous leishmaniasis. Among the isolated compounds was pentalinonsterol which has proven to be a compelling new target molecule for the treatment of leishmaniasis. Synthetic preparation and route optimization of pentalinonsterol has facilitated further in vitro and in vivo studies as well as analogue synthesis for structure activity relationship (SAR) studies. An additional focus has been on 1) compound solubility, due to pentalinonsterol’s highly lipophilic nature necessitating liposomal encapsulation for in vivo studies (the results of which have reinforced the enthusiasm for this natural product as a potential chemotherapeutic for leishmaniasis), and 2) development of probes to study mechanism of action. The analogues in development will provide a “handle” for the attachment of water soluble functional groups through a pro-drug approach and also facilitate the generation of conjugates for use as mechanistic probes. Our current strategy has focused on introducing this handle, a hydroxyl moiety, onto the core of pentalinonsterol as this approach is likely to withstand the most variability in functionality, an idea supported by preliminary SAR studies suggesting the importance of A-ring and C17 side chain functionalization for activity. Further studies will hopefully lead to the development of a new drug that is more cost effective, more potent and less toxic than current antileishmanial drugs.



pentalinonsterol, leishmaniasis, Pentalinon andrieuxii, natural product synthesis