In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin.

ABSTRACT: Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM anal

SUBMITTER: Dong LB 

PROVIDER: S-EPMC5421316 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature