Procyanidin B6

Phenylbenzopyrone of Flavonoids as a Potential Scaffold to Prevent SARSCoV-2 Replication by Inhibiting its M(PRO) Main Protease.[Pubmed:33504301]

Curr Pharm Biotechnol. 2021;22(15):2054-2070.

BACKGROUND: In December 2019, an outbreak of a pneumonia-like illness, Corona virus disease 2019 (COVID-19), originating from Wuhan, China, was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (M(PRO)) remains the most validated pharmacological target for the design and discovery of inhibitors. OBJECTIVE: The purpose of the study was to find a prospective natural scaffold as an inhibitor for M(PRO) main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelfinavir. METHODS: Natural compound libraries were screened for potential scaffold against M(PRO) main protease. Molecular dynamics simulation, MM-GBSA and principal component analyses of enzyme- ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir. RESULTS: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with the Oglycosidic form, performing better than the corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid is a more suitable inhibitor with compounds rutin, Procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin, emerging as one of the best candidate compounds. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) and implicated in lung fibrosis. CONCLUSION: The present study on flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.

A Computational Study on the Stereo- and Regioselective Formation of the C4alpha-C6' Bond of Tethered Catechin Moieties by an Exhaustive Search of the Transition States.[Pubmed:30701979]

J Org Chem. 2019 Mar 1;84(5):2840-2849.

We previously reported the total synthesis of Procyanidin B6 by using the stereo- and regioselective C-C bond formation of tethered catechin moieties as the key step. The reaction afforded the product bearing a new C4alpha-C6' bond linkage instead of the inherently preferable C4alpha-C8' bond. However, the origin of this selectivity remained unclear due to the complex structure of the substrate. Here we report the results of computational exploration of this C-C bond formation to gain mechanistic insights into the selectivity. The computational study of highly flexible compounds was realized by an exhaustive search of transition states. A large library of candidate transition states was generated by a conformational search of constrained models using molecular mechanics simulations and semiempirical molecular orbital calculations. Subsequent DFT-based transition state calculations provided 367 transition states for C4-C6' and C4-C8' bond formations. Comparison of the geometries and energies showed that the C4alpha-C6' linkage is preferentially formed via two competing transition states, leading to a C6'-diastereomeric mixture. Interactive atomic distances and visualization of the nonbonding interactions suggest the importance of nonclassical hydrogen bonding and CH-pi, pi-pi, and lone pair-pi interactions in stabilizing the two transition states. The present study supports preferential C4alpha-C6' bond formation of the tethered catechins.

Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation.[Pubmed:29346322]

Molecules. 2018 Jan 18;23(1). pii: molecules23010205.

Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of Procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3'4'-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the "regio-controlled" synthesis of Procyanidin B6. The 5-hydroxyl group of the 7,3',4'-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,3',4'-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl(4)-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position.

A seco-catechin cyclization approach to 4-->6-linked catechin dimers.[Pubmed:25296616]

Chem Commun (Camb). 2014 Nov 28;50(92):14371-3.

A viable route has been developed for the selective synthesis of the 4-->6-linked catechin dimers, scarcely accessible from Nature and/or through synthesis. An acyclic nucleophilic catechin precursor (seco-catechin) was used for the regioselective union with an electrophilic catechin unit, and subsequent pyran cyclization gave the desired 4-->6-linked dimers, i.e., Procyanidin B6 and catechin-(4alpha-->6)-gallocatechin.

First regiocontrolled synthesis of procyanidin B6, a catechin dimer with rare connectivity: a halo-capping strategy for formation of 4,6-interflavan bonds.[Pubmed:23625307]

Chem Commun (Camb). 2013 Jun 7;49(45):5210-2.

The first regiocontrolled synthesis of Procyanidin B6, a dimer with a rare 4,6-interflavan linkage, is described. Regioselective linking was achieved by the halo-capping strategy followed by removal of all the benzyl protecting groups and the halo-caps by one-pot hydrogenolysis.