Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.
Basic Information
ID: ALA1250522
Journal: Bioorg Med Chem
Title: Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.
Authors: Sun L, Veith JM, Pera P, Bernacki RJ, Ojima I.
Abstract: Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, that is, REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive and drug-resistant human cancer cell lines. MD simulation study on the paclitaxel mimics 1 and 2 as well as REDOR-Taxol bound to the 1JFF tubulin structure was quite informative to evaluate the level of mimicking. The MD simulation study clearly distinguishes the 5-6-6 and 5-7-6 tricyclic scaffolds, and also shows substantial difference in the conformational stability of the tubulin-bound structures between 2 and REDOR-Taxol. The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics.
CiteXplore: 20800500
DOI: 10.1016/j.bmc.2010.07.069
Patent ID: ┄