Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds.
Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.
Mizushina
Yoshiyuki
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
Kuramochi
Kouji
K
Ikawa
Hiroshi
H
Kuriyama
Isoko
I
Shimazaki
Noriko
N
Takemura
Masaharu
M
Oshige
Masahiko
M
Yoshida
Hiromi
H
Koiwai
Osamu
O
Sugawara
Fumio
F
Kobayashi
Susumu
S
Sakaguchi
Kengo
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D019384:Nucleic Acid Synthesis Inhibitors; D011090:Polyenes / Q000737:chemistry* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate; D059005:Topoisomerase II Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004852:Epoxy Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D011090:Polyenes; D059005:Topoisomerase II Inhibitors; C095351:epolactaene; D013755:Tetradecanoylphorbol Acetate