NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells

Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. MetAP2 is overexpressed in human colon cancer. In this report we screened various MetAP2 inhibitors and treated HT29 cells with various concentrations of compounds. We evaluated the expression of MetAP2 and pp60c-src expressions in HT29 cells. In addition we also carried out the cell proliferation and cell cycle analysis in the MetAP2 inhibitor-treated HT29 cells. The cell cycle analysis of HT29 treated with 1.0 μM of NC2213 showed an arrest in the G2 phase followed by an induction in the percentage of cells undergoing apoptosis in the sub-G1 phase. Western blot analysis revealed that the MetAP2 expression was dose-dependently decreased when the HT29 cells were treated with the 3,5-bis(benzylidene)-4-piperidone derivative (NC2213). In addition, phosphorylation of Src, a myristoylated oncoprotein was significantly decreased by 1.0 μM of NC2213 as revealed by Western blot analysis. Furthermore, NC2213 also inhibits the expression of pp60c-src in HT29 cells. Interestingly, this compound also inhibits the phosphorylation at Tyr416 of pp60c-src while increasing the phosphorylation at Tyr527 of pp60c-src. NC2213 inhibits the growth of HT29 cells by inducing apoptosis and might be useful for the treatment of human colon cancer

Global Topology and Local Violation of Discrete Symmetries

Cosmological models that are locally consistent with general relativity and the standard model in which an object transported around the universe undergoes P, C and CP transformations, are constructed. This leads to generalization of the gauge fields that describe electro-weak and strong interactions by enlarging the gauge groups to include anti-unitary transformations. Gedanken experiments show that if all interactions obey Einstein causality then P, C and CP cannot be violated in these models. But another model, which would violate charge superselection rule even for an isolated system, is allowed. It is suggested that the fundamental physical laws must have these discrete symmetries which are broken spontaneously, or they must be non causal.Comment: 12 pages, 1 figure, latex, Revtex. Charge conjugation which is physically implemented in a cosmology with the appropriate topology is described in more detail. Some minor errors are corrected. Shortened to meet the page limit of Physical Review Letters to which this paper was submitte

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Efficient synthesis of β-lactam containing α-hydroxy phosphonates using tartaric acid and fumaric acid as mild catalysts

<p>A short and efficient protocol for the synthesis of β-lactam containing α-hydroxy phosphonate esters using inexpensive catalysts such as tartaric acid and fumaric acid is described.</p

Synthesis of N-Benzylated Anilines from the Reaction of Anilines and Benzyl Chloroformate

Reactions of benzyl chloroformate with a series of substituted anilines produced N-carbobenzyloxy -œCBZ- products along with the unexpected N-benzylated -œBn- compounds. Reaction of aniline, 1a, gave the CBZ, or 2a, and Bn, or 3a, products in 29% and 14% yield, respectively. For 2-nitro-, 2-bromo-, and 2-bromo-5-nitroanilines, the N-benzylated compounds were produced exclusively. However, 2-methoxy-, 4-bromo, 4-iodo, and 4-ethylanilines gave mainly CBZ products. Other compounds reported in this study gave mixtures of the two products. For 4-chloro-3-nitroaniline, in addition to the Bn and CBZ products (53% and 14% yield, respectively), a N,N-dibenzylated product was isolated in 27% yield. Collectively, the results indicated that electron-withdrawing groups, particularly at the ortho position, directed the formation of Bn compounds, whilst electron-donating groups, especially at the ortho and para positions, favored the synthesis of CBZ products