Synthesis of Novel Phthalazinedione-Based Derivatives with Promising Cytotoxic, Anti-bacterial, and Molecular Docking Studies as VEGFR2 Inhibitors.

The parent ester methyl-3-[2-(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy)-acetylamino] has 18 compounds. The starting material for alkanoates, their corresponding hydrazides, hydrazones, and dipeptides were produced by chemoselective O-alkylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione with ethyl chloroacetate(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy) acetic acid methyl ester. The starting ester was hydrazinolyzed, then azide coupled with amino acid ester hydrochloride to produce several parent esters, and then hydrazinolyzed to produce parent hydrazides. These hydrazides were used to make a series of dipeptides by reacting them with amino acid ester hydrochloride under azide coupling conditions, and they were also condensed with a number of aldehydes to make the hydrazones. These derivatives were subjected to cytotoxicity against HCT-116 and MDA-MB-231 cells and anti-bacterial and molecular docking studies. Results indicated that the tested compounds, especially 7c and 8b with the phenyl phthalazinone moieties, had promising cytotoxicity against the HCT-116 cells with IC50 values of 1.36 and 2.34 µM, respectively. Additionally, the promising compounds 7c and 8b exhibited poor cytotoxicity against WISH cells with much higher IC50 values, so they were safe against normal cells. Compound 8c exhibited potent anti-bacterial activity with inhibition zones of 12 and 11 mm against Staphylococcus aureus and Escherichia coli, respectively. The molecular docking results of compounds 7c and 8b revealed a good binding disposition and the ligand-receptor interactions like the co-crystallized ligand of the VEGFR2 protein, which may be the proposed mode of action. Finally, compounds 7c and 8b exhibited good ADME pharmacokinetics with good drug-likeness parameters. Hence, detailed studies for the mechanism of action of such compounds are highly recommended for the development of new potent anti-cancer and anti-bacterial agents.

Anti-islet Cell Antibodies in a Sample of Egyptian Females with Gestational Diabetes and its Relation to Development of Type 1 Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus is any degree of glucose intolerance with first diagnosis during pregnancy; it affects 3-10% of pregnancies. The presence of diabetes-related autoantibodies has shown to be able to predict the development of type 1 diabetes before hyperglycemia arises. OBJECTIVE: To recognize the prevalence of islet cell antibodies among a sample of Egyptian females with gestational diabetes and its possible relation to development of Type 1 diabetes within one year postpartum. METHODS: Our cross sectional study was conducted on 150 Egyptian pregnant females with gestational diabetes aged 19-39 years diagnosed by 75-g 2-hour oral glucose tolerance test. All females were subjected to full history, thorough clinical examination and laboratory measurement of anti-islet cell antibodies. Those females with positive antibodies were followed up six months and one year after delivery for their fasting insulin, fasting blood glucose and two hours post prandial glucose levels. RESULTS: The prevalence of pregnant females with gestational diabetes having positive anti islet cell antibodies was (44%), the prevalence of females diagnosed to have diabetes mellitus was (37.88%) six months and (51.52%) one year postpartum. CONCLUSION: The high prevalence of ICAs among pregnant Egyptian females with GDM and the risk of developing type 1diabetes later in life makes screening for ICA among women with GDM important to recognize those at risk of developing type 1 diabetes later in life.

A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration.

UNLABELLED: During liver development and regeneration, hepatocytes undergo rapid cell division and face an increased risk of DNA damage associated with active DNA replication. The mechanism that protects proliferating hepatocytes from replication-induced DNA damage remains unclear. Nucleostemin (NS) is known to be up-regulated during liver regeneration, and loss of NS is associated with increased DNA damage in cancer cells. To determine whether NS is involved in protecting the genome integrity of proliferating hepatocytes, we created an albumin promoter-driven NS conditional-null (albNS(cko) ) mouse model. Livers of albNS(cko) mice begin to show loss of NS in developing hepatocytes from the first postnatal week and increased DNA damage and hepatocellular injury at 1-2 weeks of age. At 3-4 weeks, albNS(cko) livers develop bile duct hyperplasia and show increased apoptotic cells, necrosis, regenerative nodules, and evidence suggestive of hepatic stem/progenitor cell activation. CCl4 treatment enhances degeneration and DNA damage in NS-deleted hepatocytes and increases biliary hyperplasia and A6(+) cells in albNS(cko) livers. After 70% partial hepatectomy, albNS(cko) livers show increased DNA damage in parallel with a blunted and prolonged regenerative response. The DNA damage in NS-depleted hepatocytes is explained by the impaired recruitment of a core DNA repair enzyme, RAD51, to replication-induced DNA damage foci. CONCLUSION: This work reveals a novel genome-protective role of NS in developing and regenerating hepatocytes.