Analogues of chloramphenicol: circular dichroism spectra, inhibition of ribosomal peptidyltransferase, and possible mechanism of action

Circular dichroism spectra of series of chloramphenicol derivatives la-r were measured in water at pH 7. Compounds 1a-o exhibit two positive Cotton effects at 310--340 and 240--260 nm, respectively, and a weaker negative Cotton effect at 280--300 nm. In analogues 1c, 11, and 1m there is only a minimum between the two positive Cotton effects. Derivatives 1p--r possess a strong negative Cotton effect at ca. 280 nm. Compounds 1a--r were examined as inhibitors of the puromycin reaction with Escherichia coli 70S ribosome-poly(U)-N-AcPhe-tRNA complex. Analogues 11, 1n, lo, and lq are potent competitive inhibitors of puromycin comparable to or better than chloramphenicol (1b). Compounds 1k and 1m are less active, whereas 1d--g and 1j are only moderately effective. The rest of the analogues have marginal or no activity. The results are compared with previous biological data and discussed in terms of a retro-inverso relationship of chloramphenicol (1b) to the aminoacyl moiety of puromycin (aminoacyl-tRNA) and to a hypothetical transition state of peptide bond formation.