Products Cited in Publications Worldwide Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Gardner, Eric D.; Dimas, Dustin A.; Finneran, Matthew C.; Brown, Sara M.; Burgett, Anthony W.; Singh, Shanteri

DOI: PMID:

Abstract

Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization However, the inability to perform late-stage modification of the indole ring has limited the structure-activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20-50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.

Keywords

biocatalysts ; chemoenzymatic synthesis ; late-stage functionalization ; prenyltransferase ; tryprostatin

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