A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.

Intramolecular allenolate acylations in studies toward a synthesis of FR182877.

During our efforts to synthesize the cytotoxic natural product FR182877, we discovered intramolecular reductive acylations that offer a stereocontrolled alternative to the classical Knoevenagel condensation for the formation of alpha-alkylidene beta-keto-delta-lactones. Other progress toward a synthesis of FR182877 includes a pi-allyl Stille coupling and a bromo Horner-Wadsworth-Emmons reaction that forms a 12-membered ring. Structural relationships among FR182877, hexacyclinic acid, macquarimicin A, and cochleamycin A are also discussed. [reaction: see text]

Postulated biogenesis of WS9885B and progress toward an enantioselective synthesis.

[formula: see text] WS9885B promotes the assembly of microtubules in vitro and displays cytotoxicity as potent as paclitaxel against several cancer cell lines. In this Letter, we propose a biogenesis for this architecturally complex bacterial metabolite from a much simpler, polyunsaturated precursor. We also present significant progress toward a convergent, enantioselective synthesis of WS9885B. Our work features a chemoselective palladium-catalyzed cross-coupling of two advanced building blocks and an uncommon Claisen-like cyclization.