Virtual screening targeting the urokinase receptor (uPAR) led to (3R)-4-cyclohexyl-3-(hexahydrobenzo[d][1,3]dioxol-5-yl)-N-((hexahydrobenzo[d][1,3]dioxol-5-yl)methyl)butan-1-aminium 1 (IPR-1) and 4-(4-((3,5-dimethylcyclohexyl)carbamoyl)-2-(4-isopropylcyclohexyl)pyrazolidin-3-yl)piperidin-1-ium 3 (IPR-69). Synthesis of an analog of 1, namely 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC50 near 30 μM. Both compounds blocked angiogenesis with IC50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed lead-like properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 hours. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.

BackgroundType 2 diabetes mellitus (T2D), a metabolic disorder characterized by insulin resistance and relative insulin deficiency, is a complex disease of major public health importance. Its incidence is rapidly increasing in the developed countries. Complex diseases are caused by interactions between multiple genes and environmental factors. Most association studies aim to identify individual susceptibility single markers using a simple disease model. Recent studies are trying to estimate the effects of multiple genes and multi-locus in genome-wide association. However, estimating the effects of association is very difficult. We aim to assess the rules for classifying diseased and normal subjects by evaluating potential gene-gene interactions in the same or distinct biological pathways.ResultsWe analyzed the importance of gene-gene interactions in T2D susceptibility by investigating 408 single nucleotide polymorphisms (SNPs) in 87 genes involved in major T2D-related pathways in 462 T2D patients and 456 healthy controls from the Korean cohort studies. We evaluated the support vector machine (SVM) method to differentiate between cases and controls using SNP information in a 10-fold cross-validation test. We achieved a 65.3% prediction rate with a combination of 14 SNPs in 12 genes by using the radial basis function (RBF)-kernel SVM. Similarly, we investigated subpopulation data sets of men and women and identified different SNP combinations with the prediction rates of 70.9% and 70.6%, respectively. As the high-throughput technology for genome-wide SNPs improves, it is likely that a much higher prediction rate with biologically more interesting combination of SNPs can be acquired by using this method.ConclusionsSupport Vector Machine based feature selection method in this research found novel association between combinations of SNPs and T2D in a Korean population.

A direct cross-coupling between sodium sulfinates and 2H-indazoles has been developed under electrochemical conditions. The utilization of a graphite anode and platinum cathode in an undivided cell with a constant current of 7 mA allowed the concurrent oxidations of sulfinates and 2H-indazoles to sulfonyl radical and radical cationic 2H-indazoles, facilitating the direct radical–radical coupling strategy to 3-sulfonylated 2H-indazole derivatives. The transition-metal- and redox-reagent-free synthetic approach should serve as a valuable synthetic tool to achieve heteroaromatic compounds.

The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR•uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis.

A direct acyl radical addition to 2 H-indazoles has been achieved for the first time, where the less-aromatic quinonoid 2 H-indazoles readily accepted radical species to the C-3 position. Motivated by the lack of direct acylation strategy for 2 H-indazoles, the current method utilizes the radical acceptability of 2 H-indazoles, discovering an ambient temperature reaction to provide facile access to a diverse array of 3-acyl-2 H-indazoles with three points of structural diversification in 25%-83% yields.

The elimination pathway of stereochemically defined β-halovinyl ketones has been investigated using a mild base, NEt(3), leading to the formation of allenyl ketones and propargyl ketones. A preferential α-vinyl enolization of (E)-β-chlorovinyl ketones has been observed where a nonplanar s-cis conformation is proposed as a dominant conformation as opposed to a planar s-cis conformation of (Z)-β-chlorovinyl ketones. Other eliminative pathways, such as concerted syn- and anti-E2 as well as γ-deprotonation, are excluded on the basis of the deuterium isotope studies. The synthetic utility of the elimination reaction of β-chlorovinyl ketones was further demonstrated for a one-pot synthesis of 2,5-disubstituted furans in the presence of 1 mol % CuCl.

The cooperative catalyst activity between a chiral transition-metal catalyst and an achiral organocatalyst has been identified as one of the critical asymmetric reaction optimization components in the highly diastereo- and enantioselective aldol reaction of methyl α-isocyanoacetate.

[reaction: see text] The stereoselective aldol reaction of 3-silyloxyfurans with aldehydes in the presence of a Lewis acid is described. N-Bromosuccinimide (NBS)-mediated cyclization of the aldol product leads to the formation of the 2,7-dioxa-bicyclo[2.2.1]heptan-3-one ring system, which represents the formal product of hetero Diels-Alder reaction of the furan with the aldehyde.