Molecular design of cholesterols as inhibitors of DNA polymerase alpha.
The triterpenoid structure is a promising motif for the molecular design of DNA polymerase inhibitors.(1) In this study, 2-(cholesteryloxy)acetic acid (3), 2-(cholestanyl)acetic acid (7), and 2-(stigmasteryl)acetic acid (11) were found to selectively affect only DNA polymerase alpha (pol.alpha). The presence of a carboxyl group at position 28 appears to be essential for the inhibition of the pol.alpha activity. With pol.alpha, these compounds acted by competing with the template-primer DNA and noncompetitively with the substrate.
Oshige
Masahiko
M
Frontier Research Center for Genome & Drug Discovery, Department of Applied Biological Science, Faculty of Science and Technology, and Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba-ken 278-8510, Japan.
Kuramochi
Kouji
K
Ohta
Keisuke
K
Ogawa
Akitsu
A
Kuriyama
Hiroki
H
Sugawara
Fumio
F
Kobayashi
Susumu
S
Sakaguchi
Kengo
K
D001665:Binding Sites; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors
D004791:Enzyme Inhibitors; D059003:Topoisomerase Inhibitors; D004247:DNA; D002784:Cholesterol; D004256:DNA Polymerase I