Design and synthesis of functionalized coumarins as potential anti-austerity agents that eliminates cancer cells' tolerance to nutrition starvation.

Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells' tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC50 value of 0.44 µM, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.

Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase.

Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.

A novel serine racemase inhibitor suppresses neuronal over-activation in vivo.

Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aß peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo.

Synthesis of Potent and Selective Inhibitors of Aldo-Keto Reductase 1B10 and Their Efficacy against Proliferation, Metastasis, and Cisplatin Resistance of Lung Cancer Cells.

Aldo-keto reductase 1B10 (AKR1B10) is overexpressed in several extraintestinal cancers, particularly in non-small-cell lung cancer, where AKR1B10 is a potential diagnostic marker and therapeutic target. Selective AKR1B10 inhibitors are required because compounds should not inhibit the highly related aldose reductase that is involved in monosaccharide and prostaglandin metabolism. Currently, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (HMPC) is known to be the most potent competitive inhibitor of AKR1B10, but it is nonselective. In this study, derivatives of HMPC were synthesized by removing the 4-methoxyphenylimino moiety and replacing the benzylamide with phenylpropylamide. Among them, 4c and 4e showed higher AKR1B10 inhibitory potency (IC50 4.2 and 3.5 nM, respectively) and selectivity than HMPC. The treatments with the two compounds significantly suppressed not only migration, proliferation, and metastasis of lung cancer A549 cells but also metastatic and invasive potentials of cisplatin-resistant A549 cells.

Timed Inhibition of Orexin System by Suvorexant Improved Sleep and Glucose Metabolism in Type 2 Diabetic db/db Mice.

Sleep disturbances are associated with type 2 diabetes; therefore, the amelioration of sleep may improve metabolic disorders. To investigate this possibility, we here examined the effects of suvorexant, an antiinsomnia drug targeting the orexin system, on sleep and glucose metabolism in type 2 diabetic mice. Diabetic db/db mice had a longer wakefulness time during the resting period, as compared with nondiabetic db/m+ control mice. The single or 7-day administration of suvorexant at lights-on (ie, the beginning of the resting phase) increased nonrapid eye movement sleep time during the resting phase and, as a consequence, reduced awake time. The daily resting-phase administration of suvorexant for 2-4 weeks improved impaired glucose tolerance in db/db mice without affecting body weight gain, food intake, systemic insulin sensitivity, or serum insulin, and glucagon levels. No changes were detected in the markers of lipid metabolism and inflammation, such as the hepatic triglyceride content and Tnf-α mRNA levels in liver and adipose tissues. The improving effect of suvorexant on glucose tolerance was associated with a reduction in the expression levels of hepatic gluconeogenic factors, including phosphoenolpyruvate carboxykinase and peroxisome proliferator-activated receptor-γ coactivator-1α in the liver in the resting phase. In contrast, the daily awake-phase administration of suvorexant had no beneficial effect on glucose metabolism. These results suggest that the suvorexant-induced increase of sleep time at the resting phase improved hepatic glucose metabolism in db/db mice. Our results provide insight into the development of novel pharmacological interventions for type 2 diabetes that target the orexin-operated sleep/wake regulatory system.