Diarylheptanoid is a family of natural plant metabolites whose characteristic structural feature is the presence of two aromatic rings tethered by a linear seven-carbon chain. The diarylheptanoids exhibit a broad range of biological activities including anti-tumor, 1,2) anti-inflammatory, 3,4) anti-oxidant, 5,6) antihepatoxic, 7) antifungal, 8,9) and related effects. For instance, curcumin, a yellow pigment from tumeric (Curcuma longa, Zingiberaceae), has been shown to inhibit tumorigenesis during both initiation and promotion stages in several animal models, possibly through the inhibition of cyclooxygenase and lipoxygenase and blocking the formation of arachidonic acid metabolites. [10][11][12] It was reported that the substitution pattern on the aromatic moiety of curcumin has crucial effects on the gene expression of inducible forms of cyclooxygenase (COX-2) and nitric oxide synthase (iNOS).
13)Yakuchinone A and yakuchinone B (Fig. 1), diarylheptanoids from Alpinia oxyphylla (Zingiberaceae) have been reported to show potent anti-inflammatory and anti-tumor promotional activities through the inhibition of COX-2 and iNOS expression.14,15) Yakuchinone B and the structural analogues have been extensively studied as inhibitors of acyl-CoA: cholesterol O-acyltransferase that can be therapeutic agents for hypercholesterolemia and atherosclerosis.16) Yakuchinone B has also been reported to show inhibitory activity of tyrosinase. The a,b-unsaturated carbonyl conjugated moiety and aromatic ring of yakuchinone B play important roles in the competitive inhibition of tyrosinase.17) The overall biological activity of yakuchinone B is stronger than yakuchinone A that might come from the presence of enone group in the linker. We tried to optimize the structure of yakuchinone for the inhibitory activity of nitric oxide production in activated macrophages.The critical role of nitric oxide (NO) in various pathological conditions has led to the discovery of new therapeutic agents. NO, a gaseous free radical, is produced through the oxidation of arginine by nitric oxide synthase (NOS).18) The calcium-regulated constitutive isoforms, endothelial (eNOS) and neuronal (nNOS) have important roles in regulation of blood pressure and neurotransmission, 19) whereas the inducible isoform (iNOS) is calcium-independent and induced by LPS and various cytokines such as IFN-a, IL-1b, and TNF-a.20) Low concentrations of NO produced by iNOS possess beneficial roles in antimicrobial activity of macrophages against pathogens, 21) while the overproduction of NO and its derivatives, such as peroxynitrite and nitrogen dioxide, have been suggested to be mutagenic in vivo and to provoke the pathogenesis of septic shock and various inflammatory processes.22) Furthermore, NO and its oxidized forms have also been shown to be carcinogenic. 23) Thus, inhibitors of iNOS enzyme activity or its expression can be used as potential therapeutic tools for management of NO-related disorders.In the present study, we tried to obtain potent inhibitors of iNOS express...
