Conformation-Based Design and Synthesis of Apratoxin A Mimetics Modified at the α,β-Unsaturated Thiazoline Moiety.

Abstract

We have demonstrated design, synthesis, and biological evaluation of apratoxin A mimetics. In the first generation, the moCys moiety was replaced with seven simple amino acids as their 3D structures can be similar to that of apratoxin A. Apratoxins M1-M7 were synthesized using solid-phase peptide synthesis and solution-phase macrolactamization. Apratoxin M7, which contains a piperidinecarboxylic acid moiety, exhibited potent cytotoxicity against HCT-116 cells. In the second generation, substitution of each amino acid residue in the tripeptide Tyr(Me)-MeAla-MeIle moiety in apratoxin M7 led to the development of the highly potent apratoxin M16 possessing biphenylalanine (Bph) instead of Tyr(Me), which exhibited an IC50 value of 1.1 nM against HCT-116 cells. Moreover, compared to apratoxin A, apratoxin M16 exhibited a similarly high level of growth inhibitory activity against various cancer cell lines. The results indicate that apratoxin M16 could be a potential candidate as an anticancer agent.

• Authors: Yuichi Onda, Yuichi Masuda, Masahito Yoshida, Takayuki Doi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 15 Pg. 6751-6765 (08 10 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28682609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• Thiazoles
• apratoxin A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Depsipeptides (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Models, Molecular
• Molecular Conformation
• Molecular Mimicry
• Monte Carlo Method
• Thiazoles (chemical synthesis, chemistry, pharmacology)