Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis.

Cardiac hypertrophy is an adaptive response to stress, in order to maintain proper cardiac function. However, sustained stress leads to pathological hypertrophy accompanied by maladaptive responses and ultimately heart failure. At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in myocyte size, reactivation of the fetal gene markers, disassembly of the sarcomere and transcriptional remodelling which are regulated by heart-specific transcription factors like MEF2, GATA4 and immediate early genes like c-jun and c-fos.2. It has been explored and established that the hypertrophic process is associated by oxidative stress and mediated by pathways involving several terminal stress kinases like P38, JNK and ERK1/2. Stilbenoids are bioactive polyphenols and earlier studies have shown that imine stilbene exert cardioprotective and anti aging effects by acting as modulators of Sirt1. The present study was aimed at designing and synthesizing a series of imine stilbene analogs and investigate its anti hypertrophic effects and regulatory mechanism in cardiac hypertrophy and apoptosis. Interestingly one of the analog, compound 3e (10 µM) alleviated isoproterenol (ISO, 25 µM) induced hypertrophy in rat cardiomyocyte (H9c2) cells by showing a marked decrease in the myocyte size. Further, compound 3e also restored the cardiac function by activating the metabolic stress sensor, AMPK. Moreover, molecular docking studies showed stable binding between compound 3e and GSK3ß suggesting that compound 3e may directly regulate GSK3ß activity and ameliorate ISO-induced cardiac hypertrophy. In agreement with this, compound 3e also modulated the crosstalk of all the hypertrophy inducing terminal Kinases by bringing down the expression to near control conditions. The compound also relieved H2O2 (100 µM) mediated ROS and normalized abnormal mitochondrial oxygen demand in hypertrophic conditions indicating the possibility of the compound to show promise in playing a role in cardiac hypertrophy.

Identification of High Affinity Non-Peptidic Small Molecule Inhibitors of MDM2-p53 Interactions through Structure-Based Virtual Screening Strategies.

BACKGROUND: Approaches in disruption of MDM2-p53 interactions have now emerged as an important therapeutic strategy in resurrecting wild type p53 functional status. The present study highlights virtual screening strategies in identification of high affinity small molecule non-peptidic inhibitors. Nutlin3A and RG7112 belonging to compound class of Cis-imidazoline, MI219 of Spiro-oxindole class and Benzodiazepine derived TDP 665759 served as query small molecules for similarity search with a threshold of 95%. The query molecules and the similar molecules corresponding to each query were docked at the transactivation binding cleft of MDM2 protein. Aided by MolDock algorithm, high affinity compound against MDM2 was retrieved. Patch Dock supervised Protein-Protein interactions were established between MDM2 and ligand (query and similar) bound and free states of p53. Compounds with PubCid 68870345, 77819398, 71132874, and 11952782 respectively structurally similar to Nutlin3A, RG7112, Mi219 and TDP 665759 demonstrated higher affinity to MDM2 in comparison to their parent compounds. Evident from the protein-protein interaction studies, all the similar compounds except for 77819398 (similar to RG 7112) showed appreciable inhibitory potential. Of particular relevance, compound 68870345 akin to Nutlin 3A had highest inhibitory potential that respectively showed 1.3, 1.2, 1.16 and 1.26 folds higher inhibitory potential than Nutilin 3A, MI 219, RG 7112 and TDP 1665759. Compound 68870345 was further mapped for structure based pharamacophoric features. In the study, we report Cis-imidazoline derivative compound; Pubcid: 68870345 to have highest inhibitory potential in blocking MDM2-p53 interactions hitherto discovered.