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

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.