Bioactivity profiles of progressively ring-fluorinated cyclohexyl motifs in the WKYMVm peptide as formylpeptide FPR2 agonists and in keto-piperazines as anti-trypanosome agents.

Abstract

A series of all-cis ring fluorinated cyclohexylalanines with progressively increasing levels of vicinal fluorines, as well as 4-fluorophenylalanine and pentafluoroarylphenylalanine were introduced into the WKYMVm peptide in place of its tyrosine residue, for assays against the G-protein coupled formylpeptide receptor, FPR2. Selected all-cis ring cyclohexylalanines of this class were also incorporated into a keto-piperazine molecular scaffold to generate sp3 rich derivatives for assays against the parasite Trypanosoma. brucei. For these cyclohexylalanine analogues bioactivity trends correlated progressively with the levels of fluorination in each of the case studies. Notably, the all-cis pentafluorocyclohexylalanine analogue of the W-peptide was least active perhaps correlating with the well-known polarity of this 'Janus face' cyclohexane. Although the trend was also apparent in the anti-trypanosomal assays of the keto-piperazine derivatives, it was less so and some compounds were more active than the previously reported phenylalanine derived analogue.