- Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity
-
One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ~5.0 ? in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1–42) fibrillization. Furthermore, compound 2 effectively dissociated the Aβ(1–42) preformed fibrils. The cytotoxicity induced by Aβ(1–42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aβ transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aβ(1–40) were demonstrated by using electrospray ionization?traveling wave ion mobility?mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aβ(1–40)?2 complex.
- Tu, Ling-Hsien,Tseng, Ning-Hsuan,Tsai, Ya-Ru,Lin, Tien-Wei,Lo, Yi-Wei,Charng, Jien-Lin,Hsu, Hua-Ting,Chen, Yu-Sheng,Chen, Rong-Jie,Wu, Ying-Ta,Chan, Yi-Tsu,Chen, Chang-Shi,Fang, Jim-Min,Chen, Yun-Ru
-
-
Read Online
- Disubstituted aryl compound and application thereof
-
The invention relates to bis-substituted aryl compounds and application thereof. The structure of the bis-substituted aryl compounds is disclosed as Formula I, II or III. The experimental verification detects that the bis-substituted aryl compounds can be
- -
-
Paragraph 0163-0165
(2019/08/06)
-
- Curcuminoid Demethylation as an Alternative Metabolism by Human Intestinal Microbiota
-
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.
- Burapan, Supawadee,Kim, Mihyang,Han, Jaehong
-
p. 3305 - 3310
(2017/05/01)
-
- Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor
-
Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed.
- Endo, Hitoshi,Nikaido, Yuri,Nakadate, Mamiko,Ise, Satomi,Konno, Hiroyuki
-
supporting information
p. 5621 - 5626
(2015/01/08)
-
- Synthesis and evaluation of curcumin derivatives toward an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1
-
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.
- Konno, Hiroyuki,Endo, Hitoshi,Ise, Satomi,Miyazaki, Keiki,Aoki, Hideo,Sanjoh, Akira,Kobayashi, Kazuya,Hattori, Yasunao,Akaji, Kenichi
-
p. 685 - 690
(2014/01/23)
-
- Synthesis of natural and non-natural curcuminoids and their neuroprotective activity against glutamate-induced oxidative stress in HT-22 cells
-
A strategy for the synthesis of natural and non-natural 5-deoxy-6,7-dihydrocurcuminoids (diarylheptanoids) was developed for the preparation of 14 compounds with varying aromatic substituent patterns and a different functionality in the aliphatic seven-carbon chain. The in vitro protective activity against glutamate-induced neuronal cell death was examined in the murine hippocampal cell line HT-22 to find structural motifs responsible for neuroprotective effects in vitro. Among the tested compounds the ferulic acid-like unit, present in the structures of (E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hept-1-en-3-one (5) and (E)-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hept-1-en-3-one (7), appeared to be an important feature for protection against glutamate-induced neurotoxicity. Both compounds demonstrated significant neuroprotective activity in a concentration range between 1 and 25 ~M without showing toxic effects in a cytotoxicity assay with HT-22 cells. Furthermore, (E)-1,7-bis(3,4-dihydroxyphenyl)hept-1-en-3-one (9), exhibiting a caffeic acid-like structural motif, displayed a neuroprotective activity at a nontoxic concentration of 25 ~M. In contrast, (1E,6E)-1,7-bis(3,4-dihydroxyphenyl)hepta-1,6-diene-3,5-dione (4, di-O-demethylcurcumin) showed mainly cytotoxic effects. A corresponding single-ring analogue that contains the ferulic acid-like unit as an enone was not active.
- Jirsek, Petr,Amslinger, Sabine,Heilmann, J?rg
-
p. 2206 - 2217
(2014/12/11)
-
- Curcuminoid analogs inhibit nitric oxide production from LPS-activated microglial cells
-
The chemically modified analogs, the demethy-lated analogs 4-6, the tetrahydro analogs 7-9 and the hexahydro analogs 10-12, of curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) were evaluated for their inhibitory activity on lipopolysaccharide activated nitric oxide (NO) production in HAPI microglial cells. Di-O-demethylcurcumin (5) and O- demethyldemethoxycurcumin (6) are the two most potent compounds that inhibited NO production. The analogs 5 and 6 were twofold and almost twofold more active than the parent curcuminoids 1 and 2, respectively. Moreover, the mRNA expression level of inducible NO synthase was inhibited by these two compounds. The strong neuroprotective activity of analogs 5 and 6 provide potential alternative compounds to be developed as therapeutics for neurological disorders associated with activated microglia. The Japanese Society of Pharmacognosy and Springer 2011.
- Tocharus, Jiraporn,Jamsuwan, Sataporn,Tocharus, Chainarong,Changtam, Chatchawan,Suksamrarn, Apichart
-
body text
p. 400 - 405
(2012/09/10)
-
- Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species
-
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.
- Changtam, Chatchawan,de Koning, Harry P.,Ibrahim, Hasan,Sajid, M. Sohail,Gould, Matthew K.,Suksamrarn, Apichart
-
experimental part
p. 941 - 956
(2010/04/24)
-
- Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity
-
Curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3), the curcuminoid constituents of the medicinal plant Curcuma longa L., have been structurally modified to 55 analogs and antimycobacterial activity against Mycobacterium tuberculosis has been evaluated. Among the highly active curcuminoids, the isoxazole analogs are the most active group, with mono-O-methylcurcumin isoxazole (53) being the most active compound (MIC 0.09 μg/mL). It was 1131-fold more active than curcumin (1), the parent compound, and was approximately 18 and 2-fold more active than the standard drugs kanamycin and isoniazid, respectively. Compound 53 also exhibited high activity against the multidrug-resistant M. tuberculosis clinical isolates, with the MICs of 0.195-3.125 μg/mL. The structural requirements for a curcuminoid analog to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group on another aromatic ring enhances the biological activity.
- Changtam, Chatchawan,Hongmanee, Poonpilas,Suksamrarn, Apichart
-
scheme or table
p. 4446 - 4457
(2010/10/19)
-
- Antioxidant capacity of curcumin-directed analogues: Structure-activity relationship and influence of microenvironment
-
Curcumin is the active ingredient of turmeric powder with a variety of biological activities including antioxidative activity. In order to find more active antioxidants with curcumin as the lead compound we synthesised a series of enone analogues of curcumin. The present work studied and compared the capacity of curcumin-directed analogues to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH{radical dot}) and protect human red blood cells (RBCs) from oxidative haemolysis. It was found that these compounds which bear o-diphenoxyl and o-dimethoxyphenoxyl groups exhibited significantly higher DPPH{radical dot}-scavenging and anti-haemolysis activities than those which bear no such groups. In contrast to curcumin analogues that retained the 7-carbon spacer, the compounds with a 5-carbon linker had lower activity. In the case of the latter, the introduction of a ring further decreased DPPH{radical dot}-scavenging activity. However, the introduction of a ring did increase anti-haemolysis activity, suggesting that the lipophilicity of these compounds might play an important role in the antioxidant activity.
- Shang, Ya-Jing,Jin, Xiao-Ling,Shang, Xian-Ling,Tang, Jiang-Jiang,Liu, Guo-Yun,Dai, Fang,Qian, Yi-Ping,Fan, Gui-Juan,Liu, Qiang,Zhou, Bo
-
experimental part
p. 1435 - 1442
(2012/01/04)
-
- PROCESS FOR PRODUCING ENRICHED FRACTIONS OF TETRAHYDROXYCURCUMIN AND TETRAHYDROTETRAHYDROXY-CURCUMIN FROM THE EXTRACTS OF CURCUMA LONGA
-
A process for producing an enriched fraction of tetrahydoxycurcumin containing, tetrahydroxycurcumin, demethylcurcumin, demethylmonodemethoxycurcumin and bisd.emethoxycurcumin and colorless tetrahydroderivatives thereof. The process consists of demethylation of natural curcumins, obtained, in turn, from the organic solvent extract of turmeric from Curcuma species. The said enriched fraction of tetrahydroxycurcumin is subjected to hydrogenation to get colorless tetrahydrotetrahydroxycurcumin enriched fraction. The enriched fractions of tetrahydroxycurcumin and colorless tetrahydrotetrahydroxycurcumin exhibits potent antioxidative action and reduces inflammation.
- -
-
Page/Page column 13
(2008/06/13)
-
- Synthesis and biological evaluation of polyhydroxycurcuminoids
-
A series of curcumin analogs (1-3, 5a-5t) was synthesized through the condensation of appropriately protected hydroxybenzaldehydes with acetylacetone, followed by deprotection. The antioxidant activity of these analogs was determined by superoxide free radical nitroblue tetrazolium and DPPH free radical scavenging methods and the polyhydroxycurcuminoids (5l-5s) displayed excellent antioxidant activity. These analogs showed cytotoxicity to lymphocytes and promising tumor-reducing activity on Dalton's lymphoma ascites tumor cells.
- Venkateswarlu, Somepalli,Ramachandra, Marellapudi S.,Subbaraju, Gottumukkala V.
-
p. 6374 - 6380
(2007/10/03)
-
- Antitumor agents. Part 214: Synthesis and evaluation of curcumin analogues as cytotoxic agents
-
Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound 50 was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and 0.63 μg/mL, respectively.
- Ishida, Junko,Ohtsu, Hironori,Tachibana, Yoko,Nakanishi, Yuka,Bastow, Kenneth F,Nagai, Masahiro,Wang, Hui-Kang,Itokawa, Hideji,Lee, Kuo-Hsiung
-
p. 3481 - 3487
(2007/10/03)
-
- Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action
-
We have previously reported the inhibitory activity of curcumin against human immunodeficiency virus type one (HIV-1) integrase. In the present study, we have synthesized and tested analogs of curcumin to explore the structure-activity relationships and mechanism of action of this family of compounds in more detail. We found that two curcumin analogs, dicaffeoylmethane (6) and rosmarinic acid (9), inhibited both activities of integrase with IC50 values below 10 μM. We have previously demonstrated that lysine 136 may play a role in vital DNA binding. We demonstrated equivalent potencies of two curcumin analogs against both this integrase mutant and wild-type integrase, suggesting that the curcumin-binding site and the substrate-binding site may not overlap. Combining one curcumin analog with the recently described integrase inhibitor NSC 158393 resulted in integrase inhibition which was synergistic, reflective of drug-binding sites which may not overlap. We have also determined that these analogs can inhibit binding of the enzyme to the viral DNA but that this inhibition is independent of divalent metal ion. Furthermore, kinetic studies of these analogs suggest that they bind to the enzyme at a slow rate. These studies can provide mechanistic and structural information which may guide the future design of integrase inhibitors.
- Mazumder, Abhijit,Neamati, Nouri,Sunder, Sanjay,Schulz, Jutta,Pertz, Heinz,Eich, Eckart,Pommier, Yves
-
p. 3057 - 3063
(2007/10/03)
-