Development of fluorinated ripostatins as RNA-polymerase inhibitors and potential atibiotics
Final Report Abstract
As a result of our studies, an efficient synthetic approach to various fluorinated analogues of ripostatin A containing heterocyclic fragments in the side chain was developed. The synthetic pathway is modular and features a last-stage click-chemistry derivatization of a common advanced intermediate. The produced compounds were found to be less potent than derivatives of ripostatin B, but still active against some organisms. We also performed optimization studies on the catalytic aldol reaction of difluoroketene silyl acetal. Additionally, we produced some building blocks for ripostatin analogues with bioisosters of the exocyclic carboxylic group and investigated partial hydrogenation of macroalctone with diimide. Further studies on the SAR of ripostatins with modifications around the macrolactone fragment may produce more promising compounds suitable for the development into clinical candidates.
Publications
- “Synthesis and biological evaluation of fluorinated analogues of ripostatin A”, Org. Biomol. Chem., 2019, 17, 1362-1364
V. Shenderman, E. V. Prusov
(See online at https://doi.org/10.1039/c8ob02890g)
