Probing a distinct druggable tubulin binding site with gatorbulins 1-7, their metabolic and physicochemical properties, and pharmacological consequences.

ABSTRACT: Microtubules, consisting of α/β-tubulin heterodimers, are prime targets for anticancer drug discovery. Gatorbulin-1 (GB1, 1a) is a recently described marine natural product that targets tubulin at a new, seventh pharmacological site at the tubulin intradimer interface. Using our previously developed robust route towards GB1 (1a), we synthesized simplified, first-generation gatorbulins, GB2-7 (1b-1g) of this highly modified cyclodepsipeptide (GB1) that does not contain any proteinogenic amino acid. We systematically investigated the structure-activity relationship at the biochemical and cellular level using GB1-susceptible ovarian and cervical cancer cells. We validated that the hydroxamate moiety in the N-methyl-alanine residue is critical for activity. All other structural modifications p

SUBMITTER: Chen QY 

PROVIDER: S-EPMC11995438 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature