Taxol derivatives are selective inhibitors of DNA polymerase alpha.
During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase alpha (pol.alpha) and beta (pol.beta). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.alpha and beta. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.alpha activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.beta inhibitors. With both pol.alpha and beta, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate.
Oshige
Masahiko
M
Frontier Research Center for Genome & Drug Discovery, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Takenouchi
Mika
M
Kato
Yasutaro
Y
Kamisuki
Sinji
S
Takeuchi
Toshifumi
T
Kuramochi
Kouji
K
Shiina
Isamu
I
Suenaga
Yoshihito
Y
Kawakita
Yo-ichi
Y
Kuroda
Kazufumi
K
Sato
Noriyuki
N
Kobayashi
Susumu
S
Sugawara
Fumio
F
Sakaguchi
Kengo
K
D000818:Animals; D045744:Cell Line, Tumor; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D026942:DNA Topoisomerases / Q000187:drug effects; D004330:Drosophila / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids / Q000302:isolation & purification / Q000494:pharmacology*; D020946:Taxus / Q000737:chemistry
D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D043823:Taxoids; C473166:taxinine; D004256:DNA Polymerase I; D026942:DNA Topoisomerases; D017239:Paclitaxel