Unlocking New Prenylation Modes: Azaindoles as a New Substrate Class for Indole Prenyltransferases

• DOI: 10.1002/cctc.202300650
• Publication Date: 2023-08-10T17:28:26Z
• Authors: Eric D. Gardner; Bryce P. Johnson; Dustin A. Dimas; Heather E. McClurg; Zachary C. Severance; Anthony W. Burgett; Shanteri Singh
• Keywords: Prenyltransferase

Abstract Aza‐substitution, the replacement of aromatic CH groups with nitrogen atoms, is an established medicinal chemistry strategy for increasing solubility, but current methods accessing functionalized azaindoles are limited. In this work, indole‐alkylating prenyltransferases (PTs) were explored as a to directly functionalize azaindole‐substituted analogs natural products. For this, series aza‐L‐tryptophans (Aza‐Trp) featuring N ‐substitution every position indole ring and their corresponding cyclic Aza‐L‐Trp‐L‐proline dipeptides (Aza‐CyWP), synthesized substrate mimetics PTs FgaPT2, CdpNPT, FtmPT1. We then demonstrated most these accepted by PT, regioselectivity each prenylation was heavily influenced ‐substitution. Remarkably, FgaPT2 found produce cationic ‐prenylpyridinium products, representing not only new class also previously unobserved mode. The discovery that nitrogenous bioisosteres can be thus provides access unavailable chemical space in search bioactive indolediketopiperazine analogs.