RESUMO
An expedient cyclopropanation of α-methylene-ß-lactams with α-ketoesters mediated by P(NMe2)3 has been developed. This reaction enables rapid access to a series of functionalized spirocyclopropyl ß-lactams in good yields from bench-stable starting materials under mild conditions. The experimental results indicated that the C3-substituent of the α-methylene-ß-lactam not only significantly impacted the reaction efficiency and stereochemistry but also played a pivotal role in determining the chemoselectivity of the reaction.
RESUMO
Genetic association analysis and functional analysis have suggested that telomerase reverse transcriptase (TERT) gene affects the predisposition to various tumors. In this study, we wanted to explore the association between TERT variants and hepatocellular carcinoma (HCC) risk in a Han Chinese population via a case-control study of 473 HCC patients and 564 controls. Sequenom Mass-ARRAY platform was applied to determine the genotype of TERT polymorphisms in these subjects. Odds ratios and 95% confidence intervals that calculated by logistic regression analysis were used to assess the association under the genotype, dominant, recessive, and additive models. The "AA" genotype frequency of TERT rs2242652 in cases was significantly lower than in controls (1.69% versus 3.72%). We found two SNPs were associated with decreased risk of HCC with or without the adjustment for age and gender: rs10069690 under an additive model (adjusted OR = 0.77, 95% CI: 0.60-0.98, P = 0.038); rs2242652 under a dominant model (adjusted OR = 0.72, 95% CI: 0.54-0.95, P = 0.022) and an additive model (adjusted OR = 0.72, 95% CI: 0.56-0.92, P = 0.009). To our knowledge, the present study is the first to show the significant association between TERT polymorphisms and HCC susceptibility in a Han Chinese population from China, which may act as a potential prognostic biomarker in HCC patients.
RESUMO
The embryonic mouse muscle nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel formed by alpha1, beta1, delta, and gamma subunits. The receptor contains two ligand binding sites at alpha/delta and alpha/gamma subunit interfaces. [(3)H]Curare preferentially binds the alpha/gamma interface. We describe the synthesis and properties of a high-affinity iodinated ligand that selectively binds the alpha/delta interface. An analogue of alpha-conotoxin MI was synthesized with an iodine attached to Tyr-12 (iodo-alpha-MI). The analogue potently blocks the fetal mouse muscle subtype of nAChR expressed in Xenopus oocytes. It failed, however, to block alpha3beta4, alpha4beta2, or alpha7 nAChRs. Iodo-alpha-MI potently blocks the alpha1beta1delta but not the alpha1beta1gamma subunit combination expressed in Xenopus oocytes indicating selectivity for the alpha/delta subunit interface. Alpha-conotoxin MI was subsequently radioiodinated, and its properties were further evaluated. Saturation experiments indicate that radioiodinated alpha-conotoxin MI binds to TE671 cell homogenates with a Hill slope of 0.95 +/- 0.0094. Kinetic studies indicate that the binding of [(125)I]alpha-conotoxin MI is reversible (k(off) = 0.084 +/- 0.0045 min(-1)); k(on) is 8.5 x 10(7) min(-1) M(-1). The calculated k(d) is 0.98 nM. This potency is approximately 20-fold higher than the unmodified alpha-MI peptide. Unlike [(125)I]alpha-bungarotoxin, [(125)I]alpha-conotoxin MI binding to TE671 cell homogenates is fully displaceable by the small molecule antagonist d-tubocurarine.