In vitro and in silico perspectives to explain anticancer activity of a novel syringic acid analog ((4-(1H-1, 3-benzodiazol-2-yl)-2, 6-dimethoxy phenol)) through apoptosis activation and NFkB inhibition in K562 leukemia cells.

Syringic acid (SA) is an active carcinogenesis inhibitor; however, the low bioavailability and unstable functional groups hinder its activity. Here, a chemically synthesized novel SA analog (SA10) is evaluated for its anticancer activity using in-vitro and in-silico studies. K562 cell line study revealed that SA10 had shown a higher rate of inhibition (IC50 = 50.40 µg/mL) than its parental compound, SA (IC50 = 96.92 µg/mL), at 50 µM concentration. The inhibition ratio was also been evaluated by checking the expression level of NFkB and Bcl-2 and showing that SA10 has two-fold increase in the inhibitory mechanism than SA. This result demonstrates that SA10 acts as an NFkB inhibitor and an apoptosis inducer. Further, molecular docking and simulation have been performed to get insights into the possible inhibitory mechanism of SA and SA10 on NFkB at the atomistic level. The molecular docking results exemplify that both SA and SA10 bind to the active site of NFkB, thereby interfering with the association between DNA and NFkB. SA10 exhibits a more robust binding affinity than SA and is firmly docked well into the interior of the NFkB, as confirmed by MM-PBSA calculations. In a nutshell, the Benzimidazole scaffold containing SA10 has shown more NFkB inhibitory activity in K562 cells than SA, which could be helpful as an ideal therapeutic NFkB inhibitor for treating cancers.

Protective effects of syringic acid, resveratrol and their combination against isoprenaline administered cardiotoxicity in wistar rats.

OBJECTIVE: To evaluate the cardio-protection of syringic acid (SA) in combination with resveratrol (RV) in isoproterenol (ISO) induced myocardial infarcted (MI) rats. METHODS: Groups of all rats were subjected oral pre-treatment at the beginning of the study with SA (50 mg/kg), RV (50 mg/kg) and combination (COMB) of SA (25 mg/kg) and RV (25 mg/kg) along with gallic acid (GA) (50 mg/kg) for 30 days. After sacrification, homogenate of heart tissue along with serum were utilized for further biochemical investigations. The effects on creatine kinase (CK), aspartate transaminase (AST), alanine transaminase (ALT) and gamma glutamyl transferase (GGT) were studied in serum and heart tissues. Glutathione-s-transferase (GST), glutathione peroxidase (GPX) and reduced glutathione (GSH), membrane bound enzymes and electrolytes were tested in heart tissues. Body weights and heart weights were also observed along with high sensitivity C-reactive protein (hs-CRP), uric acid and total protein content (TPC) in serum. RESULTS: CK, AST, ALT and GGT levels in serum were augmented significantly while these enzymes are decreased in cardiac tissue samples of ISO-treated rats. GST, GPX, GSH, Na+/K+, Mg2+, Ca2+ ATPases, K+ ions were significantly decreased while Na+ and Ca2+ ions were increased in the heart tissues of ISO-injected rats. Loss and gain of body and heart weights were noticed significantly in rats having ISO administration. ISO group showed significant increase in hs-CRP and Uric acid while significant decrease in TPC. All of actions of ISO were ameliorated by COMB. CONCLUSIONS: COMB suppressed ISO induced MI in rats and exhibited cardio-protection.

A new insight into identification of in silico analysis of natural compounds targeting GPR120.

G-protein coupled receptor (GPR120) is an omega-3 fatty acid receptor that inhibits macrophage-induced tissue inflammation. Recent studies revealed GPR120 promotes colorectal carcinoma through modulation of VEGF, IL-8, PGE2, and NF-kB expression. However, three-dimensional structure of GPR120 is not yet available in Protein Data Bank (PDB). In the present study, we focused on a 3-D structural model of GPR120 has been constructed using homology modeling techniques. The structural quality of the predicted GPR120 model was verified using Procheck, Whatif, ProSA, and Verify 3D. After this chemical database of natural compounds have been constructed and screened for its druggability using molinspiration server. Molecular docking studies of natural compounds on GPR120 model revealed that silibinin (- 6.87 kcal/mol), withanolide (- 6.19 kcal/mol), limonene (- 6.17 kcal/mol), and cervical (- 6.15 kcal/mol) have shown good docking interactions with active site residues of the target. Active site residues of Arg280, Asp275, and Gly122 showed hydrogen-bonding interactions with predicted compounds. Based on these in silico findings, we proposed that virtual screening of natural compounds against of GPR120 is a novel approach to find potential anti-colorectal cancer therapeutics.

Design and screening of syringic acid analogues as BAX activators-An in silico approach to discover "BH3 mimetics".

Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach. Results from the docking studies revealed that, SA1, SA9, SA10, SA14 and SA21 analogues have shown good interaction with BAX trigger site, of which SA10 and SA14 bound specifically with Lys21 at α1 helix of BAX, a critical residue involved in BAX activation. All docking calculations of SA analogues were compared with clinically tested BH3 mimetics. In this entire in silico study, SA analogous have performed an ideal binding interactions with BAX compared to BH3 mimetics. Further, in silico point mutation of BAX-Lys21 to Glu21 resulted in structural change in BAX and showed reduced binding energy and hydrogen bond interactions of the selected ligands. Based on these findings, we propose that virtual screening and mutation analysis of BAX is found to be the critical advance method towards the discovery of novel anticancer therapeutics.

Exploring the Binding Affinity of Novel Syringic Acid Analogues and Critical Determinants of Selectivity as Potent Proteasome Inhibitors.

Syringic acid, a known plant phenolic compound and its analogues are known to possess high proteasome inhibitory activity. In the current work, we describe synthesis, characterization, DFT, docking of syringic acid (SA) and analogues (SAA1 and SAA2) and biological effects were studied. Syringic acid and its analogues were docked for the first time with the crystal structures of ß5 proteasome of diverse eukaryotic organisms. Among all proteasomes, the humanoid proteasome showed the highest degree of docking conformation and low inhibition constant (Ki). SAA2 specifically displayed binding to the N-terminal Thr1 residue in the S1 pocket of Mus musculus ß5 proteasome along with threonine, lysine and arginine; conventionally involved major amino acid residues in ligand binding. The geometrical properties (B3LYP/6- 31g (d, p)) and electrostatic potentials of molecules were computed using DFT calculations. A detailed molecular picture of the compounds and its interactions was obtained from NBO analysis. SA-analogues elucidated potent antioxidant activities and good antibacterial activity. In-vitro DNA binding studies revealed that all molecules had strong binding at the major groove of dsDNA. In the view of medical applicability, proteasome inhibition is an important therapeutic strategy for various types of cancers. Therefore, current discoveries may encourage the rational design and development of new chemical entities of syringic acid based chemotherapeutics.