Design, synthesis, and evaluation of an anti‐trypanosomal [1,2,4]triazolo[1,5‐ a ]pyrimidine probe for photoaffinity labeling studies

Lucero, Bobby, Francisco, Karol R., Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Liu, Lawrence J., Yao, Yuemang, Brancale, Andrea, Brunden, Kurt R., Caffrey, Conor R. and Ballatore, Carlo 2024. Design, synthesis, and evaluation of an anti‐trypanosomal [1,2,4]triazolo[1,5‐ a ]pyrimidine probe for photoaffinity labeling studies. ChemMedChem 19 (8) , e202300656. 10.1002/cmdc.202300656

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Abstract

Studies have shown that depending on the substitution pattern, microtubule (MT)‐targeting 1,2,4‐triazolo[1,5‐a]pyrimidines (TPDs) can produce different cellular responses in mammalian cells that may be due to these compounds interacting with distinct binding sites within the MT structure. Selected TPDs are also potently bioactive against the causative agent of human African trypanosomiasis, Trypanosoma brucei, both in vitro and in vivo. So far, however, there has been no direct evidence of tubulin engagement by these TPDs in T. brucei. Therefore, to enable further investigation of anti‐trypanosomal TPDs, a TPD derivative amenable to photoaffinity labeling (PAL) was designed, synthesized, and evaluated in PAL experiments using HEK293 cells and T. brucei. The data arising confirmed specific labeling of T. brucei tubulin. In addition, proteomic data revealed differences in the labeling profiles of tubulin between HEK293 and T. brucei, suggesting structural differences between the TPD binding site(s) in mammalian and trypanosomal tubulin.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/. This article also appears in: Society Volumes: Czech Republic
Publisher:	Wiley
ISSN:	1860-7179
Date of First Compliant Deposit:	13 February 2024
Date of Acceptance:	26 January 2024
Last Modified:	07 May 2024 14:33
URI:	https://orca.cardiff.ac.uk/id/eprint/166274

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