Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.
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.
Sun
Liang
L
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Veith
Jean M
JM
Pera
Paula
P
Bernacki
Ralph J
RJ
Ojima
Iwao
I
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D017239:Paclitaxel / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D017239:Paclitaxel
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