Jiraporn Ungwitayatorn

Molecular docking study on anticancer activity of plant-derived natural products

A variety of compounds from plant sources have been reported to possess substantial anticancer properties; however, their modes of action have not been clearly defined. Selected plant-derived compounds that exhibit anticancer activity were subjected to docking simulations using AutoDock 3.0.5. To preliminarily investigate the potential molecular targets and to confirm the experimental activity testing for these anticancer compounds, the docking was performed using different enzymes and receptor proteins involved with cell cycle, cell growth, and DNA replication, i.e., cyclin-dependent protein kinase 2 (CDK-2), CDK-6, DNA topoisomerases I and II, B-cell lymphoma 2 (Bcl-2), vascular endothelial growth factor receptor 2 (VEGFR-2), and the telomere: G-quadruplexes. The docking results revealed that lupeol exhibited better binding interaction to CDK-2 and Bcl-2 than the known CDK-2 and Bcl-2 inhibitors. Epigallocatechin gallate (EGCG) was found to bind to CDK-6 with tighter interaction than several reported CDK-6 inhibitors. Flavopiridol, a synthetic flavonoid, was best bound to DNA topoisomerase I. Green tea catechin was best docked with topoisomerase II and VEGFR-2 and quercetin showed very good binding interaction with telomere: G-quadruplex. The experimental-derived inhibition constant (Ki) against Bcl-2 and Ki calculated from docking energy were well correlated. Therefore, the calculated Ki could be used as a preliminary tool for screening of Bcl-2 inhibitors before performing experimental activity assay.

In Vitro Antioxidant Activity Study of Novel Chromone Derivatives

Forty‐eight chromone derivatives were evaluated for their antioxidant activity using 2,2‐diphenyl‐1‐picrylhydrazyl free radical scavenging assay, ferrous ions (Fe2+) chelating activity test, total antioxidant activity test (Ferric thiocyanate and Thiobarbituric acid methods), and total reductive capability (potassium ferricyanide reduction). 7,8‐Dihydroxy‐2‐(3′‐trifluoromethylphenyl)‐3‐(3″‐trifluoromethylbenzoyl) chromone 32 showed stronger radical scavenging and metal chelating activities than butylated hydroxytoluene, vitamin E, and trolox. Chromone derivatives that exhibited good radical scavenging and metal chelating also displayed strong total antioxidant and reductive power activities. The results obtained from this study indicated that the synthesized chromone derivatives have remarkable antioxidant activity.

MANGANIC ACETATE MEDIATED TRANSFORMATION OF ENOL-ETHERS INTO GAMMA-LACTONES

Abstract Manganic acetate and potassium methyl malonate with a 2-substituted dihydropyran provide the corresponding fused gamma-lactone in good yield. Carboxylic acids with less acidic methylene protons fail in this reaction.

Quantitative structure-activity relationship (QSAR) study of polyhydroxyxanthones

In the present study 13C-chemical shift additivity rules are developed for polyhydroxyxanthones with antituberculotic activity against Mycobacterium tuberculosis. QSAR investigations are performed by correlating 13C-chemical shifts and calculated dipole moments of several 1,3-substituted polyhydroxyxanthones with their antituberculotic activity and by using the CoMFA approach as a three-dimensional QSAR method.

3D-QSAR studies on chromone derivatives as HIV-1 protease inhibitors: application of molecular field analysis.

Three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models were developed for chromone derivatives against HIV‐1 protease using molecular field analysis (MFA) with genetic partial least square algorithms (G/PLS). Three different alignment methods: field fit, pharmacophore‐based, and receptor‐based were used to derive three MFA models. All models produced good predictive ability with high cross‐validated r2 (r2cv), conventional r2, and predictive r2 (r2pred) values. The receptor‐based MFA showed the best statistical results with r2cv = 0.789, r2 = 0.886, and r2pred = 0.995. The result obtained from the receptor‐based model was compared with the docking simulation of the most active compound 21 in this chromone series to the binding pocket of HIV‐1 protease (PDB entry 1AJX). It was shown that the MFA model related well with the binding structure of the complex and can provide guidelines to design more potent HIV‐1 protease inhibitors.

Design and synthesis of a bicyclic non-peptide β-bend mimetic of enkephalin

Abstract If the important functional groups of a biologically active peptide can be arrayed on a non-peptide framework in the “biologically active conformation” it may be possible to maximize the receptor interaction and eliminate or reduce the number of amide bonds that are available for proteolytic enzyme cleavage. Thus, we have designed and synthesized the 2,5,7-substituted 2,3,4,4a,7,7a-hexahydro-pyranol[2,3-b]pyrrole ring system as the basis for non-peptide mimetic analogs for peptides that prefer the β-bend conformation. Computer assisted molecular modeling studies have indicated that the resulting analogs closely resemble the functional group positioning particularly of type I and I′ peptide β-bends. Completed analogs of Leu-enkephalin have been synthesized and shown to be potent naloxone-reversible agonists in the electrically stimulated guinea pig ileum assay.

Ligand-based CoMFA and CoMSIA studies on chromone derivatives as radical scavengers

The antioxidant activity for a series of chromone compounds, evaluated by DPPH free radical scavenging assay, were subjected to 3D-QSAR studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). All 48 chromone derivatives were geometry optimized by AM1 and HF/6-31G(*) calculations. The CoMFA and CoMSIA results were compared between different alignment strategies. The best CoMFA model obtained from HF/6-31G(*) optimization with field fit alignment gave cross-validated r(2) (q(2))=0.821, noncross-validated r(2)=0.987, S=0.095, and F=388.255. The best CoMSIA model derived from AM1 optimized structures and superimposition alignment gave q(2)=0.876, noncross-validated r(2)=0.976, S=0.129, and F=208.073, including electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The contour maps provide the fruitful structure-radical scavenging activity relationships which are useful for designing new compounds with higher activity.

Antimalarial activity of HIV-1 protease inhibitor in chromone series

Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65μM), was found to be the most potent antimalarial compound with IC50=0.95μM while primaquine and tafenoquine showed IC50=2.41 and 1.95μM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=-13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent.

Molecular docking studies of chromone derivatives against wild type and mutant strains of HIV-1 protease

Abstract Developing a new HIV-1 protease (HIV-1 PR) inhibitor is still a challenging task to overcome the drug resistance mutations in the HIV-PR. In this study, docking simulations of chromone derivatives against wild type and eleven mutant variants HIV-1 PR were investigated using GOLD and Autodock programs. From both GOLD and Autodock results, chromone 3, the experimentally observed highly potent HIV-1 PR inhibitor, showed stronger binding affinity against every studied mutant strain (2AVS, 2AVO, 2AVV, 1MES, 1MET, 1MEU, 1SDU, 1SDV, 1C6Y, 2F8O, and 1SH9) than the wild-type enzyme (1AJX). Chromone 32, another potent inhibitor as well as chromones 33, 34, 37, and 47 also showed high binding interaction with several mutant-type enzymes. The coherent picture of the interactions at the active sites of mutant PR should facilitate the further design and development of new potent inhibitor against multidrug-resistant virus.

Synthesis, Topoisomerase I Inhibitory and Cytotoxic Activities of Chromone Derivatives

A series of chromone derivatives were designed as potential topoisomerase I (Top I) inhibitors based on the docking simulation study. Sixteen synthesized compounds were evaluated for Top I inhibitory activity and some compounds were further tested for in vitro cytotoxic activity. The most potent inhibitor, chromone 11b showed greater inhibitory activity (IC50 = 1.46 μM) than the known Top I inhibitors, i.e., camptothecin, fisetin and morin, but inactive against breast cancer cell (MCF-7), oral cavity cancer cell (KB) and small cell lung cancer (NCI-H187). Chromone 11c, another potent inhibitor (IC50 = 6.16 μM), exhibited cytotoxic activity against KB (IC50 = 73.32 μM) and NCI-H187 (IC50 = 36.79 μM).