Hideji Itokawa

A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.

More than 30 Curcuma species (Zingiberaceae) are found in Asia, where the rhizomes of these plants are used as both food and medicine, such as in traditional Chinese medicine. The plants are usually aromatic and carminative, and are used to treat indigestion, hepatitis, jaundice, diabetes, atherosclerosis and bacterial infections. Among the Curcuma species, C. longa, C. aromatica and C. xanthorrhiza are popular. The main constituents of Curcuma species are curcuminoids and bisabolane-type sesquiterpenes. Curcumin is the most important constituent among natural curcuminoids found in these plants. Published research has described the biological effects and chemistry of curcumin. Curcumin derivatives have been evaluated for bioactivity and structure-activity relationships (SAR). In this article, we review the literature between 1976 and mid-2008 on the anti-inflammatory, anti-oxidant, anti-HIV, chemopreventive and anti-prostate cancer effects of curcuminoids. Recent studies on curcuminoids, particularly on curcumin, have discovered not only much on the therapeutic activities, but also on mechanisms of molecular biological action and major genomic effects.

Panaxadiol, C30H52O3, a sapogenin of Ginseng roots was acetylated to afford monoacetate, C32H54O4, which was oxidized with chromium trioxide to give panaxanolone acetate, C52H52O4. On Wolff-Kishner reduction, panaxanolone acetate was converted into panaxanol, C30H52O2, which was heated with hydrochloric acid in glacial acetic acid to furnish anhydropanaxanol acetate, C32H52O2. On catalytic hydrogenation of anhydropanaxanol, isotirucallenol (X) was obtained, which was established by infrared and gaschromatography. A trimethyltetrahydropyrane ring system in panaxadiol was proved by mass-spectrometry, and the oxygen ring was cleaved by the action of hydrochloric acid on panaxanol. The α, β-unsaturated ketonic system was proved ultraviolet spectroscopically in the product derived from panaxanolone acetate by the action of sulfuric acid in glacial acetic acid. Thus the hindered hydroxyl of panaxadiol should be present at the 12-position. Consequently, it has been concluded that panaxadiol is a new tetracyclic triterpene of dammarane series having hydroxyls at the 3- and 12-positions and trimethyltetrahydropyrane ring at C(17), as represented by the formula (T).