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Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Sun L,Veith JM,Pera P,Bernacki RJ,Ojima I

doi

10.1016/j.bmc.2010.07.069

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

7101-12

issue

19

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(10)00733-9

journal_volume

18

pub_type

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