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Issue 25, 2013
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Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents

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Abstract

Reaction of 10-deacetylbaccatin III (III) and its 7-TES derivative (IV) with DAST under various conditions resulted in the formation of an array of new fluorinated and non-fluorinated 13-keto taxoid compounds (2a–4a) through a vinylogous pinacol–pinacolone rearrangement. Further fluorination of some of these products (2a, 3a) with NFSi or Selectfluor gave additional derivatives. Sodium borohydride reduction of the 13-keto group of these products (2a, 2b, 3a, 3b, 4a, 8, 9, 11–14) led to a series of 9α-hydroxy taxoid derivatives, which were esterified using the docetaxel side chain employing the corresponding protected β-lactam, followed by deprotection to furnish a library of docetaxel analogs and related compounds. A selected number of synthesized compounds (7, 10, 19a, 19b, 21a, 21b, 23, 27, 29, 34–36) were submitted to the National Cancer Institute (NCI) 60 cell line screening program and tested for cytotoxic properties. Taxoids 19a, 19b, 21a, 21b, 23, 27, 29, 34 and 35 were found to exhibit significant anticancer activity against various cancerous cell lines with 23, 27, and 29 being the most potent compounds, demonstrating GI50 values of ≤5 nM in several assays.

Graphical abstract: Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents

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Publication details

The article was received on 02 Apr 2013, accepted on 03 May 2013 and first published on 17 May 2013


Article type: Paper
DOI: 10.1039/C3OB40654G
Citation: Org. Biomol. Chem., 2013,11, 4154-4163
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    Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents

    K. C. Nicolaou and R. A. Valiulin, Org. Biomol. Chem., 2013, 11, 4154
    DOI: 10.1039/C3OB40654G

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