Design, Synthesis, and Evaluation of An Anti-trypanosomal [1,2,4]Triazolo[1,5-a]pyrimidine Probe for Photoaffinity Labeling Studies.

Autor: Lucero B; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Francisco KR; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Varricchio C; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF103NB, U.K., Liu LJ; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Yao Y; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania, 19104, USA., Brancale A; Vysoká Škola Chemicko-Technologická v Praze, Department of Organic Chemistry, Technická 5, Prague, 16628, Czech Republic., Brunden KR; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania, 19104, USA., Caffrey CR; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Ballatore C; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Apr 16; Vol. 19 (8), pp. e202300656. Date of Electronic Publication: 2024 Feb 12.
DOI: 10.1002/cmdc.202300656
Abstrakt: 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.
(© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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