5-Substituted pyrido[2,3-d]pyrimidine,an inhibitor against three receptor tyrosine kinases

NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N′-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 μM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3′-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.     

Manganese-based complexes of radical scavengers as neuroprotective agents

Manganese was incorporated in the structure of the selected antioxidants to mimic the superoxide dismutase (SOD) and to increase radical scavenging ability. Five manganese complexes (1-5) showed potent SOD activity in vitro with IC(50) of 1.18-1.84 microM and action against lipid peroxidation in vitro with IC(50) of 1.97-8.00 microM greater than their ligands and trolox. The manganese complexes were initially tested in vivo at 50 mg/kg for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mice brain. Only manganese complexes of kojic acid (1) and 7-hydroxyflavone (3) exhibited the significant suppressions on MAP-induced hypermotility and did not significantly decrease the locomotor activity in normal condition. Manganese complex 3 also showed protective effects against learning and memory impairment in transient cerebral ischemic mice. These results supported the brain delivery and the role of manganese in SOD activity as well as in the modulation of brain neurotransmitters in the aberrant condition. Manganese complex 3 from 7-hydroxyflavone was the promising candidate for radical implicated neurodegenerative diseases.     

Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity

In this study, three manganese complexes of curcumin (Cp) and related compounds, diacetylcurcumin (AcylCp) and ethylenediamine derivative (CpED), were synthesized and evaluated in vitro for antilipid peroxidation and superoxide dismutase activity. The manganese complexes exhibited a great capacity to protect brain lipids against peroxidation with IC₅₀ of 6.3–26.3 μM. All manganese complexes showed much greater SOD activity than their corresponding antioxidant ligands as well as trolox with IC₅₀ values of 8.9–29.9 μM. AcylCp and curcumin manganese complexes (AcylCpCpx and CpCpx) also gave the highest inhibitory activity to H₂O₂-induced cell damage (oxidative stress) at 0.1 μg/ml (< 0.2 μM) in NG108-15 cells, which were more potent than curcumin and related compounds. The neuropharmacological tests in mice supported the idea that the SOD mimicking complexes were able to penetrate to the brain as well as their role in the modulation of brain neurotransmitters under the aberrant conditions. The complexes significantly improved the learning and memory impairment induced by transient ischemic/reperfusion. AcylCpCpx, CpCpx, and CpEDCpx showed significant protection at 6.25, 25, and 50 mg/kg (i.p.), respectively, whereas manganese acetate and curcumin had no effect at doses of 50 mg/kg. In addition, treatment of AcylCpCpx and curcumin significantly attenuated MPTP-induced striatal dopamine depletion in mice, which was in accordance with the increase in the density of dopaminergic neurons when compared with MPTP-treated mice. These results support the important role of manganese in importing SOD activity and consequently, the enhancement of radical scavenging activity. AcylCpCpx and CpCpx seem to be the most promising neuroprotective agents for vascular dementia.     

Novel inhibitor for fibroblast growth factor receptor tyrosine kinase

NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 0.4 microM but with similar potency as SU16g. NP603 inhibited the tyrosine phosphorylation in FGF receptor and the activation of extracellular signal-regulated kinase and c-Jun-N-terminal-kinase after the rhFGF-2 stimulation. The increase in activity of NP603 supports the role of Lys514 movement in ligand-receptor binding in modeling study as the movement accommodates the hydrophobic interaction at the receptor pocket leading to the enhancement of binding capacity.     

Aquatic Ecosystem Impacts of Land Sharing Versus Sparing: Nutrient Loading to Southeast Asian Rivers

As world food demand continues to increase, two broad strategies for agricultural production have been widely discussed: land sparing and land sharing. Reflecting tradeoffs between the extent and intensity of agricultural use, land sparing maximizes the ratio of conserved to agricultural land, whereas land sharing allows more extensive, nature-friendly transformation of the agroecological matrix. Freshwater ecosystems are rarely considered in weighing these strategies, despite being strongly affected by land-use change. Here we analyze how shifting from extensive to intensive agricultural practices is altering dry season riverine nutrient availability and algal growth in upland Southeast Asia, which is experiencing rapid conversion from swidden—or shifting—cultivation to fertilized row crops. In situ algal growth assays and nutrient concentration data from eleven catchments representing a spectrum of land use and population densities show that intensive agriculture is associated with significantly elevated nitrate concentrations but no shift in phosphorus. As a result, nitrogen to phosphorus ratios increases dramatically, shifting algal growth toward colimitation by nitrogen and phosphorus. Geochemical analysis of suspended solids suggested comparable geological inputs across basins, but dissolved rare earth elements reveal that inorganic fertilizers are changing water chemistry in parallel with land use. Taken together, our analyses suggest that the transition from low-input land-sharing management (swidden) to high-input land-sparing practices (intensive row-crop agriculture) underway in Southeast Asia has profound consequences for river ecosystems. Such nutrient loading can affect river productivity and food webs, suggesting that land-use conservation strategies for Southeast Asia need to account for impacts on freshwater ecosystems.