Screening and evaluation of new inhibitors of hepatic glucose production.
In the course of our screening program for inhibitors of hepatic glucose production in rat hepatoma H4IIE-C3 cells, which were used as model liver cells, five naphtoquinone derivatives-javanicin, solaniol, 9-O-methylfusarubin, 5,10-dihydroxy-1,7-dimethoxy-3-methyl-1H-naphtho[2,3-c]pyran-6,9-dione, 9-O-methylbostrycoidin-and vanillin were selected from our natural product library. These naphtoquinone derivatives inhibited hepatic glucose production at IC(50) values of 3.8-29 microM, but showed cytotoxicity against hepatic cells after incubation for 48 h. However, vanillin showed an IC(50) value of 32 microM without exhibiting cytotoxicity at 50 microM. Therefore, we examined 12 vanillin derivatives to investigate their inhibitory activities against glucose production. Among these analogs, 4-hydro-3-methoxyacetophenone and 5-nitrosalicylaldehyde exhibited stronger inhibition than the other compounds at IC(50) values of 25 and 24 microM, respectively, with no cytotoxicity at a concentration of 50 microM. Hence, 4-hydro-3-methoxyacetophenone and 5-nitrosalicylaldehyde may be useful as a lead compound of anti-type 2 diabetic drugs.
Hashimoto
Junko
J
Biomedicinal Information Research Center (BIRC), Japan Biological Informatics Consortium (JBIC), Koto-ku, Tokyo, Japan.
Motohashi
Keiichiro
K
Sakamoto
Kazutoshi
K
Hashimoto
Seiichi
S
Yamanouchi
Maasa
M
Tanaka
Hiroshi
H
Takahashi
Takashi
T
Takagi
Motoki
M
Shin-ya
Kazuo
K
D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000096:biosynthesis*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D051381:Rats
D001547:Benzaldehydes; D007004:Hypoglycemic Agents; D009285:Naphthoquinones; C100058:vanillin; D005947:Glucose