Abstract
Curcumin has diverse biological activities, but is known to undergo rapid metabolism via reduction of vinylic double bonds and phase II conjugation. To prevent reductive metabolism of curcumin, we introduced a methyl group at both C2 and C6 positions (compound 1) or at the C2 position (compound 2) of curcumin, creating steric hindrance on double bonds against metabolizing enzymes. As predicted, these compounds were resistant to reduction by alcohol dehydrogenase. Compound 1 was further evaluated for its antiangiogenesis activity in vitro and in vivo. It exhibited significantly greater inhibitory activity than curcumin against endothelial cell migration, invasion, and tube formation. Similarly, the in vivo Matrigel plug assay in C57BL/6 mice showed more pronounced reduction of blood vessels in the plugs containing 1 than those containing curcumin. Moreover, 1 suppressed tumor growth more effectively than curcumin in a U87MG mouse xenograft model by inhibiting angiogenesis. In vivo metabolite analysis by liquid chromatography/mass spectrometry demonstrated that 1 underwent markedly slower reductive metabolism than curcumin. Taken together, our results indicate that 1 has enhanced antiangiogenesis activity and suppression of tumor growth compared with curcumin, reflecting diminished reductive metabolism owing to the introduction of methyl groups at the C2 and C6 positions of curcumin.
Highlights
That curcumin undergoes biotransformation into hexahydrocurcumin (HHC) and hexahydrocurcuminol when incubated with human or rat hepatocytes and analyzed using high performance liquid chromatography (HPLC) (280 nm) and mass spectrometry (MS), with more rapid metabolism observed in rat hepatocytes[12]
We designed and synthesized novel curcumin derivatives substituted with a methyl group for the hydrogen on both C2 and C6 positions or the C2 position only of the 5-hydroxy-1,4,6-heptatrien3-one backbone
Two curcumin derivatives substituted with a methyl group at both C2 and C6 positions and at the C2 position only were designed and synthesized
Summary
That curcumin undergoes biotransformation into hexahydrocurcumin (HHC) and hexahydrocurcuminol when incubated with human or rat hepatocytes and analyzed using high performance liquid chromatography (HPLC) (280 nm) and mass spectrometry (MS), with more rapid metabolism observed in rat hepatocytes[12]. Another study has shown that curcumin incubated with intestinal and hepatic cytosols is metabolized to HHC, tetrahydrocurcumin (THC) and curcumin sulfate, human and rat cytosols show differences in ability to metabolize curcumin to its reduction and conjugation products[13]. After intravenous (i.v.; 40 mg/kg) or oral (500 mg/kg) administration of curcumin to rats, HPLC analysis by UV absorption at 420 nm showed curcumin glucuronide and sulfate as the major metabolites in rat plasma. Whether the anticancer activity of curcumin derives from the compound itself or its metabolites is not fully understood, a study has shown that curcumin inhibits 12-O-tetradecanoylphorbol13-acetate-induced tumor promotion in a carcinogen-initiated mouse skin, whereas THC has lower activity[16], suggesting that the activity may not be attributable to the reductive metabolite. The doubly substituted derivative (1) was further explored for its antiangiogenesis activity in vitro and for its antitumor activity as well as metabolism in a U87MG mouse xenograft model
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