Syntheses of taxuspine C derivatives as functional inhibitors of P-glycoprotein, an ATP-associated cell-membrane transporter.
UV-Irradiation of taxinine and related compounds in acetonitrile induced a smooth transannulation between the C-3 and C-11 positions without any influence from the C-2, C-9 and C-10 substituents to give tetracyclic taxuspine C derivatives in almost quantitative yields. Photochemical transannular reaction of taxoids possessing a cinnamoyl group in the side-chain was accompanied by an E,Z-isomerization of the cinnamoyl moiety. Cellular accumulation of vincristine, a useful drug for cancer chemotherapy, in multidrug-resistant ovarian cancer cells was found to increase most effectively in the case of 5-O-benzoylated 5-O-decinnamoyltaxuspine C. This indicates that the 5-O-benzoylated taxuspine C derivative may be a promising functional inhibitor of P-glycoprotein, which acts as an ATP-associated efflux pump for cancer chemotherapeutic agents.
Sako
M
M
Gifu Pharmaceutical University, Japan.
Suzuki
H
H
Hirota
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000528:radiation effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003640:Dealkylation; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D010777:Photochemistry; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D014750:Vincristine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D000255:Adenosine Triphosphate; D017239:Paclitaxel