NaClO‐Mediated Cross Installation of Indoles and Azoles Benefits Anticancer Hit Discovery

Abstract

Innovations in synthetic chemistry have a profound impact on the drug discovery process, and will always be a necessary driver of drug development. As a result, it is of significance to develop novel simple and effective synthetic installation of medicinal modules to promote drug discovery. Herein, we have developed a NaClO-mediated cross installation of indoles and azoles, both of which are frequently encountered in drugs and natural products. This effective toolbox provides a convenient synthetic route to access a library of N-linked 2-(azol-1-yl) indole derivatives, and can be used for late-stage modification of drugs, natural products and peptides. Moreover, biological screening of the library has revealed that several adducts showed promising anticancer activities against A549 and NCI-H1975 cells, which give us a hit for anticancer drug discovery.

Late-stage peptide modification and macrocyclization enabled by tertiary amine catalyzed tryptophan allylation

“…[22][23][24][25][26][27][28][29][30] However, the reported methods require harsh reaction conditions, such as high temperatures, oxidant additives, auxiliary directing groups, and complex reaction conditions, which restrict their application prospects in bioactive peptide research. With the development of photochemistry in recent years, radicalmedicated C2 amination, [31][32][33] uoroalkylation, 34,35 alkylation, 36,37 and thiation 38,39 on the indole ring of tryptophan have been explored for the functionalization of peptides. In sharp contrast, modication on the NH position of the indole ring of Trp is much less explored due to the lower nucleophilicity and basicity of indole N-H of Trp among the multiple nucleophilic sites in peptide.…”

“…In line with our ongoing interest in peptide chemistry, including those Trp modications, 33,39,42,[45][46][47][48][49] we have been trying to explore more mild, easy-to-manipulate alternatives for peptide modication/functionalization to enrich the scenario. Promoted by our previous work on organocatalytic indole functionalization 50,51 and Morita-Baylis-Hillman (MBH) carbonate based allylation, [52][53][54] and inspired by Chen's N-allylic alkylation of indoles with MBH carbonates, 55 we sought to explore the reaction between Trp and MBH carbonates to develop a novel strategy for peptide functionalization.…”

Michael Addition Reaction between Dehydroalanines and Phosphites Enabled the Introduction of Phosphonates into Oligopeptides

“…In line with our recent late-stage peptide modification efforts, − including those based on Dha, − and antimicrobial peptide development, − we sought to develop a rapid and facile method for peptide phosphorylation using the P Michael addition of readily available phosphites to the Dha residue, which would be a novel strategy for the screening of potential antimicrobial phosphopeptide hits (Scheme B).…”