title: 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 analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Liao-Bin
authors.initials: LB
authors.lastname: Dong
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rudolf
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States. Electronic address: cameron@scripps.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States; Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States; Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States. Electronic address: shenb@scripps.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis* / Q000494:pharmacology*; D062365:Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D000627:Aminophenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D014508:Urea / Q000737:chemistry*
chemical_list: D062365:Aminobenzoates; D000627:Aminophenols; D000813:Anilides; D000900:Anti-Bacterial Agents; D002219:Carbamates; D011083:Polycyclic Compounds; D014508:Urea; D000218:Adamantane; C510909:platensimycin; C520340:platencin
keywords: Amide hydrolysis; Fatty acid synthase inhibitors; Natural products; Platencin; Platensimycin; Urea and carbamate analogues