Design of Coibamide A Mimetics with Improved Cellular Bioactivity

  • ACS Med Chem Lett. 2021 Dec 29;13(1):105-110. doi: 10.1021/acsmedchemlett.1c00591.
Takashi Kitamura  1 ,  Rikito Suzuki  1  2 ,  Shinsuke Inuki  1 ,  Hiroaki Ohno  1 ,  Kerry L McPhail  3 ,  Shinya Oishi  1  2
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 2. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States.
PMID: 35059129 DOI: 10.1021/acsmedchemlett.1c00591
Abstract

Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure-activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.