3',4',5',3,5,6,7-Heptamethoxyflavone

DMC (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) improves glucose tolerance as a potent AMPK activator.[Pubmed:26975545]

Metabolism. 2016 Apr;65(4):533-42.

OBJECTIVE: We investigated the effect and regulatory mechanism of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) isolated from Cleistocalyx operculatus on metabolic parameters in myotubes, adipocytes and an obese mouse model. MATERIALS AND METHODS: Myotubes and adipocytes were incubated with or without DMC. Glucose uptake, fatty acid oxidation, AMPK activation and adipocytes differentiation were investigated. To examine in vivo effect of DMC, 30mg/kg/day DMC was administered by oral gavage for 2weeks in high fat fed C57BL/6 male mice and intra-peritoneal glucose tolerance test was performed. In order to examine whether DMC directly activates AMPK, we performed cell free AMPK assay and surface plasmon resonance spectroscopy analysis. RESULT: DMC increases glucose uptake and fatty acid oxidation (FAO) in myotubes. Also, DMC inhibits adipocyte differentiation in 3T3-L1 cells. Interestingly, DMC stimulates phosphorylation of AMP-dependent protein kinase (AMPK) alpha subunit (T172) by directly binding to AMPK, which results in the activation of AMPK. Furthermore, DMC binds AMPK with a higher affinity than AMP. When AMPK was knocked down, the stimulatory effect of DMC on FAO and its inhibitory effect on adipogenesis were abolished. These results suggest that the effects of DMC were primarily mediated by AMPK activation. In addition, treating mice fed a high fat diet with DMC improved glucose tolerance and significantly increased FAO of the muscles. CONCLUSION: DMC, as a novel AMPK activator, shows anti-diabetic effects in cell culture systems, such as myotubes and adipocytes, and in a diet-induced obese mouse model.

Cytotoxic, Antiproliferative and Pro-Apoptotic Effects of 5-Hydroxyl-6,7,3',4',5'-Pentamethoxyflavone Isolated from Lantana ukambensis.[Pubmed:26690473]

Nutrients. 2015 Dec 10;7(12):10388-97.

Lantana ukambensis (Vatke) Verdc. is an African food and medicinal plant. Its red fruits are eaten and highly appreciated by the rural population. This plant was extensively used in African folk medicinal traditions to treat chronic wounds but also as anti-leishmanial or cytotoxic remedies, especially in Burkina Faso, Tanzania, Kenya, or Ethiopia. This study investigates the in vitro bioactivity of polymethoxyflavones extracted from a L. ukambensis as anti-proliferative and pro-apoptotic agents. We isolated two known polymethoxyflavones, 5,6,7,3',4',5'-hexamethoxyflavone (1) and 5-hydroxy-6,7,3',4',5'-pentamethoxyflavone (2) from the whole plant of L. ukambensis. Their chemical structures were determined by spectroscopic analysis and comparison with published data. These molecules were tested for the anti-proliferative, cytotoxic and pro-apoptotic effects on human cancer cells. Among them, 5-hydroxy-6,7,3',4',5'-pentamethoxyflavone (2) was selectively cytotoxic against monocytic lymphoma (U937), acute T cell leukemia (Jurkat), and chronic myelogenous leukemia (K562) cell lines, but not against peripheral blood mononuclear cells (PBMCs) from healthy donors, at all tested concentrations. Moreover, this compound exhibited significant anti-proliferative and pro-apoptotic effects against U937 acute myelogenous leukemia cells. This study highlights the anti-proliferative and pro-apoptotic effects of 5-hydroxy-6,7,3',4',5'-pentamethoxyflavone (2) and provides a scientific basis of traditional use of L. ukambensis.

Crystal structure of 2'-[(2',4'-di-fluoro-biphenyl-4-yl)carbon-yl]-1'-phenyl-1',2',5',6',7',7a'-hexa-h ydro-spiro-[indole-3,3'-pyrrolizin]-2(1H)-one.[Pubmed:26396754]

Acta Crystallogr E Crystallogr Commun. 2015 Jul 11;71(Pt 8):915-8.

In the title pyrrolizidine derivative, C33H26F2N2O2, both pyrrolidine rings of the pyrrolizidine moiety adopt an envelope conformation. The di-fluoro-phenyl group is oriented at an angle of 54.3 (1) degrees with respect to the oxindole moiety. The crystal packing features an N-Hcdots, three dots, centeredO hydrogen bond, which forms an R 2 (2)(8) motif, and a C-Hcdots, three dots, centeredO inter-action, which generates a C(8) chain along [010]. In addition, this chain structure is stabilized by C-Hcdots, three dots, centeredpi inter-actions. In one of the pyrrolidine rings, the methyl-ene group forming the flap of an envelope and the H atoms of the adjacent methyl-ene groups are disordered over two sets of sites, with site-occupancy factors of 0.571 (4) and 0.429 (4).

Discovery of 4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[ cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane -1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.[Pubmed:28339198]

J Med Chem. 2017 Apr 13;60(7):2819-2839.

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.