First Total Synthesis of (+)-11,11′-Dideoxyverticillin A

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shiraia bambusicolaAlthough it is ten years since the anti-cancer properties of (+)-11,11′-dideoxyverticillin A were first described, it is only now that the first total synthesis has been reported. The compound was originally isolated from the mycelium of a marine-derived fungus of the genus Penicillium and has since been found in several other fungal species including Shiraia bambusicola, a parasitic fungus which grows on some species of bamboo.

(+)-11,11'-dideoxyverticillin A structureWith ten rings and eight stereogenic centres, (+)-11,11′-dideoxyverticillin A is one of the most complex of a family of dimeric epidithiodiketopiperazine natural products. Writing in the journal Science, chemists at the Massachusetts Institute of Technology have now described an enantioselective 11-step synthesis, starting from the commercially available amino acids, tryptophan and alanine. The synthesis was designed to mimic a plausible biosynthetic pathway and, as well as providing ready access to (+)-11,11′-dideoxyverticillin A itself, should provide access to analogues which may have enhanced pharmacological activity. The elegant synthesis used a minimum of protecting groups and, by taking full advantage of the inherent reactivity of intermediates, offers insights into the natural biosynthetic pathways. (+)-11,11′-Dideoxyverticillin A inhibits the tyrosine kinase activity of the epidermal growth factor receptor with an IC50 of 0.14nM, shows anti-angiogenic activity, and prevents the growth of several cancer cell lines.


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