Design, synthesis and biological activity of protaxols.
Taxol is a product isolated from the Pacific yew tree (Taxus brevifolia) and is a potent microtubule-stabilizing agent which has recently been approved for treatment of otherwise intractable ovarian cancer. Despite taxol's therapeutic promise, its aqueous insolubility (< 0.004 mg ml-1) hampers its clinical application. Here we report the design, synthesis and biological activity of a series of taxol-releasing compounds (protaxols) with improved pharmacological properties. These prodrugs were designed to increase their aqueous solubility and allow for taxol release under basic or physiological conditions. We demonstrate the stability of these prodrugs at pH < or = 7 and their ability to release taxol in a basic medium. Taxol-like microtubule-stabilizing activity appears after the release of taxol. In vitro these prodrugs have cytotoxic properties against tumour cell lines comparable to those of taxol; moreover, human plasma catalyses the release of active taxol. These protaxols have greater potential as anticancer agents than the parent compounds taxol and taxotere (Fig. 1a).
Nicolaou
K C
KC
Department of Chemistry, Scripps Research Institute, La Jolla, California 92037.
Riemer
C
C
Kerr
M A
MA
Rideout
D
D
Wrasidlo
W
W
D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D017239:Paclitaxel