13157-90-9Relevant articles and documents
11-β-hydroxysterols as possible endogenous stimulators of mitochondrial biogenesis as inferred from epicatechin molecular mimicry
Dugar, Sundeep,Villarreal, Francisco,Hollinger, Frank H.,Mahajan, Dinesh,Ramirez-Sanchez, Israel,Moreno-Ulloa, Aldo,Ceballos, Guillermo,Schreiner, George
, (2019/11/28)
Currently, there is great interest in identifying endogenous (i.e. physiological) stimulators of mitochondrial biogenesis (MB), in particular, those that may mediate the effects of exercise. The molecular size of the cacao flavanols (epicatechin and catechin) highly resembles that of sterols and epicatechin has been reported to activate cells surface receptors leading to the stimulation of MB in endothelial and skeletal muscle cells translating into enhanced exercise capacity. We therefore hypothesize, that epicatechin may be acting as a structural mimic of an as yet unknown sterol capable of stimulating MB. We developed a new synthetic process for obtaining enantiomerically pure preparations of (-)-epicatechin and (+)-epicatechin. Applying spatial analytics and molecular modeling, we found that the two isoforms of epicatechin, (-) and (+), have a structural resemblance to 11-β-hydroxypregnenolone, a sterol with no previously described biological activity. As reported in this proof-of-concept study performed in primary cultures of endothelial and muscle cells, 11-β-hydroxypregnenolone is one of the most potent inducers of MB as significant activity can be detected at femtomolar levels. The relative potency of (-)/(+)-epicatechin isoforms and on inducing MB correlates with their degree of spatial homology towards the 11-β-hydroxypregnenolone. On the basis of these results, the detailed in vivo characterization of the potential for these sterols to act as endogenous modulators of MB is warranted.
Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors
Villaume, Sydney A.,Fu, Jian,N'Go, Inès,Liang, Hui,Lou, Huayong,Kremer, Laurent,Pan, Weidong,Vincent, Stéphane P.
supporting information, p. 10423 - 10429 (2017/08/07)
This study reports a novel class of inhibitors of uridine 5′-diphosphate (UDP) galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids are potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed a structure–activity relationship analysis to be performed and which functional groups and structural elements were required for UGM inhibition could be determined. The binding mode of one of the best inhibitors was found to be noncompetitive. Docking simulations indicated that this molecule was likely to bind UGM in its open conformation, in a cavity recently identified as a “druggable” pocket. Importantly, two of the best inhibitors of the M. tuberculosis UGM displayed moderate activity against whole M. tuberculosis cells. This study reports the first natural products that act as inhibitor of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.
NOVEL APPROACH FOR SYNTHESIS OF CATECHINS
-
Paragraph 0138; 0139; 0140; 0141, (2016/01/15)
A process for synthesis of enatiomerically pure or enatiomerically enriched or racemic mixture of (+and/or?) epicatechin echm and its intermediates, comprising the steps of: (i) obtaining penta-protected quercetin; (ii) reducing the penta-protected quercetin obtained from step (i); (iii) optionally deprotecting the compound of step (ii); (iv) reducing the compound obtained from step (ii) or step (iii) in the presence of a chiral/achiral reducing agent to obtain a chiral intermediate; (v) deprotecting and/or hydrogenation of the chiral intermediate obtained from step (iv) to obtain (?)-epicatechin; (vi) optionally simultaneously deprotecting and by drogenation of the compound obtained from step (ii) to obtain racemic epicatechin.
