Cyanopyridinone- and Cyanopyridine-Based Cancer Cell Pim-1 Inhibitors: Design, Synthesis, Radiolabeling, Biodistribution, and Molecular Modeling Simulation.

In this study, two new series of 3-cyanopyridinones (3a-e) and 3-cyanopyridines (4a-e) were synthesized and evaluated for their cytotoxicity and Pim-1 kinase inhibitory activity adopting 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and in vitro Pim-1 kinase inhibition assay, respectively. Most of the tested compounds revealed promising cytotoxicity against HepG-2, HCT-116, MCF-7, and PC-3 cell lines. Among them, compounds 4c and 4d showed more potent cytotoxicity against the HePG2 cell line with IC50 = 8.02 ± 0.38 and 6.95 ± 0.34 µM, respectively, than that of the reference 5-FU (IC50 = 9.42 ± 0.46 µM). Moreover, compound 4c was more potent against HCT-116 (IC50 = 7.15 ± 0.35 µM) than 5-FU (IC50 = 8.01 ± 0.39 µM), while compound 4d with IC50 = 8.35 ± 0.42 µM displayed comparable activity to that of the reference drug. Furthermore, high cytotoxic activity was manifested by compounds 4c and 4d against MCF-7 and PC3 cell lines. Our results have also indicated that compounds 4b, 4c, and 4d elicited remarkable inhibition of Pim-1 kinase; 4b and 4c showed equipotent inhibitory activity to that of the reference quercetagetin. Meanwhile, 4d displayed IC50 = 0.46 ± 0.02 µM, showed the best inhibitory activity among the tested compounds, and was more potent than quercetagetin (IC50 = 0.56 ± 0.03 µM). For optimization of the results, docking study of the most potent compounds 4c and 4d in the Pim-1 kinase active site was carried out and compared with both quercetagetin and the reported Pim-1 inhibitor A (VRV), and the results were consistent with those of the biological study. Consequently, compounds 4c and 4d are worthy of further investigations toward the discovery of Pim-1 kinase inhibitors as drug candidates for cancer therapy. Compound 4b was successfully radiolabeled with radioiodine-131, and its biodistribution in Ehrlich ascites carcinoma (EAC)-bearing mice showed more observable uptake in tumor sites, and hence, it can be introduced as a new radiolabeled agent for tumor imaging and therapy.

Liver transplantation at KFSHRC: achievement and challenges.

The liver transplantation program at KFSHRC has been active since 2001. More than 450 liver transplants have been performed so far. The program evolved from adult cadaveric transplant to living donor and recently to pediatric and split techniques. The 1-year survival of patients for both pediatric and adult exceeded 90% and the 5-year survival of patients is more than 80%. Associated with this success are challenges that include: organ shortage, quality of organ harvested, inability to meet the growing national need, increased demand of resource to meet the need of the program, and lack of a collaborative national strategy in organ donation and transplantation.