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, 9-0-methyifusarubin, 5,10-dihydroxy-1,7-dimethoxy-3-methyl-1H-naphtho[2,3-c]pyran-6,9-dione, 9-0-methy!bostrycoidin—and vanillin were selected from our natural product library. These naphtoquinone derivatives inhibited hepatic glucose production at IC 50 values of 3.8-29 μM, but showed cytotoxicity against hepatic cells after incubation for 48 h. However, vanillin showed an IC 50 value of 32 μM without exhibiting cytotoxicity at 50 μM. 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 μM, respectively, with no cytotoxicity at a concentration of 50 μM. Hence, 4-hydro-3-methoxyacetophenone and 5-nitrosalicylaldehyde may be useful as a lead compound of anti-type 2 diabetic drugs.