869789-09-3Relevant articles and documents
Curcuminoid Demethylation as an Alternative Metabolism by Human Intestinal Microbiota
Burapan, Supawadee,Kim, Mihyang,Han, Jaehong
, p. 3305 - 3310 (2017/05/01)
Curcumin and other curcuminoids from Curcuma longa are important bioactive compounds exhibiting various pharmacological activities. In addition to the known reductive metabolism of curcuminoids, an alternative biotransformation of curcuminoids by human gut microbiota is reported herein. A curcuminoid mixture, composed of curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (3), was metabolized by the human intestinal bacterium Blautia sp. MRG-PMF1. 1 and 2 were converted to new metabolites by the methyl aryl ether cleavage reaction. Two metabolites, demethylcurcumin (4) and bisdemethylcurcumin (5), were sequentially produced from 1, and demethyldemethoxycurcumin (6) was produced from 2. Until now, sequential reduction of the heptadienone backbone of curcuminoids was the only known metabolism to occur in the human intestine. In this study, a new intestinal metabolism of curcuminoids was discovered. Demethylation of curcuminoids produced three new colonic metabolites that were already known as promising synthetic curcumin analogues. The results could explain the observed beneficial effects of turmeric.
Synthesis and evaluation of curcumin derivatives toward an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1
Konno, Hiroyuki,Endo, Hitoshi,Ise, Satomi,Miyazaki, Keiki,Aoki, Hideo,Sanjoh, Akira,Kobayashi, Kazuya,Hattori, Yasunao,Akaji, Kenichi
, p. 685 - 690 (2014/01/23)
To research a new non-peptidyl inhibitor of beta-site amyloid precursor protein cleaving enzyme 1, we focused on the curcumin framework, two phenolic groups combined with an sp2 carbon spacer for low-molecular and high lipophilicity. The structure-activity relationship study of curcumin derivatives is described. Our results indicate that phenolic hydroxy groups and an alkenyl spacer are important structural factors for the inhibition of beta-site amyloid precursor protein cleaving enzyme 1 and, furthermore, non-competitive inhibition of enzyme activity is anticipated from an inhibitory kinetics experiment and docking simulation.
Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species
Changtam, Chatchawan,de Koning, Harry P.,Ibrahim, Hasan,Sajid, M. Sohail,Gould, Matthew K.,Suksamrarn, Apichart
experimental part, p. 941 - 956 (2010/04/24)
The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC50 for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7 μM, respectively). Among 43 curcuminoid analogs and 8 pairs of 1:1 mixture of curcuminoid analogs tested, 8 pure analogs and 5 isomeric mixtures of analogs exhibited high antitrypanosomal activity in submicromolar order of magnitude. Among these highly active analogs, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (40) was the most active compound, with an EC50 value of 0.053 ± 0.007 μM; it was about 2-fold more active than the standard veterinary drug diminazene aceturate (EC50 0.12 ± 0.01 μM). Using a previously characterized diminazene-resistant T. b. brucei (TbAT1-KO) and a derived multi-drug resistant line (B48), no cross-resistance of curcuminoids was observed to the diamidine and melaminophenyl arsenical drugs that are the current treatments. Indeed, curcuminoids carrying a conjugated keto (enone) motif, including 40, were significantly more active against T. b. brucei B48. This enone motif was found to contribute to particularly high trypanocidal activity against all Trypanosoma species and strains tested. The parent curcuminoids showed low antileishmanial activity (EC50 values of compounds 1 and 2 for Leishmania mexicana amastigotes are 16 ± 3 and 37 ± 6 μM, respectively) while the control drug, pentamidine, displayed an EC50 of 16 ± 2 μM. Among the active curcuminoid analogs, four compounds exhibited EC50 values of less than 5 μM against Leishmania major promastigotes and four against L. mexicana amastigotes. No significant difference in sensitivity to curcuminoids between L. major promastigotes and L. mexicana amastigotes was observed. The parent curcuminoids and most of their analogs were also tested for their toxicity against human embryonic kidney (HEK) cells. All the curcuminoids exhibited lower toxicity to HEK cells than to T. b. brucei bloodstream forms and only one of the tested compounds showed significantly higher activity against HEK cells than curcumin (1). The selectivity index for T. b. brucei ranged from 3-fold to 1500-fold. The selectivity index for the most active analog, the enone 40, was 453-fold.
