Embryonic exposure to acetyl-L-carnitine protects against valproic acid-induced cardiac malformation in zebrafish model.

Worldwide, estimated counts of about 7.9 million children are born with serious birth defects. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants represents a major contributing factor to congenital malformations. In earlier investigation, we explored cardiac malformation caused by valproic acid (VPA) during early developing stages of zebrafish. Since heart depends on mitochondrial fatty acid oxidative metabolism for energy demands in which carnitine shuttle has a major role, the present study aimed to investigate the effect of acetyl-L-carnitine (AC) against VPA-induced cardiac malformation in developing zebrafish. Initially, AC was subjected to toxicological evaluation, and two micromolar concentrations (25 µM and 50 µM) were selected for evaluation. A sub-lethal concentration of VPA (50 µM) was selected to induce cardiac malformation. The embryos were grouped and the drug exposures were made at 2.5 h post-fertilization (hpf). The cardiac development and functioning was monitored. A progressive decline in cardiac functioning was noted in group exposed to VPA 50 µM. At 96 hpf and 120 hpf, the morphology of heart was severely affected with the chambers which became elongated and string-like accompanied by histological changes. Acridine orange staining showed accumulation of apoptotic cells. Group exposed to VPA 50 µM with AC 50 µM showed a significant reduction in pericardial sac edema with morphological, functional and histological recovery in developing heart. Moreover, reduced number of apoptotic cells was noted. The improvement with AC might be due to restoration of carnitine homeostasis for cardiac energy metabolism in developing heart.

Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer - An in-silico approach.

BACKGROUND: Breast cancer is one of the malignant tumours which mainly affect the female population. 20% of the cases of breast cancer are due to the over-expression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role in antitumor activity due to their DNA-intercalating properties. OBJECTIVE: Some novel 9-anilinoacridines substituted with pyrazole moiety (1a-z) were designed and their HER2enzyme (PDB id-3PP0) inhibition activity was performed by molecular docking studies using the Glide module of Schrodinger suite 2019-4. METHODS: Glide module of the Schrodinger suite was used to perform docking studies; qikprop module was used for in-silico ADMET screening and the Prime-MMGBSA module was used for free binding energy calculations. Based on GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2. RESULTS: The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z exhibited a good binding affinity with Glide scores in the range of -4.9 to -9.75, when compared with the standard drugs CK0403 (-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, it was evident that most of the compounds fell within the recommended values. MM-GBSA binding calculations of the most potent inhibitors were found to be more favourable. CONCLUSION: The results of in-silico studies provide strong evidence for the potential of valuable ligands in pyrazole substituted 9-anilinoacridines as HER2 inhibitors, and the compounds, 1v,s,r,d,a,o with significant Glide scores may produce significant anti-breast cancer activity.