Sulfonamide-based non-alkyne LpxC inhibitors as Gram-negative antibacterial agents.

We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC=0.063µg/mL, K. pneumoniae MIC=0.5µg/mL, and P. aeruginosa MIC=0.5µg/mL), and is a promising lead for further exploration as an antibacterial agent.

Synthesis of ß(1,3) oligoglucans exhibiting a Dectin-1 binding affinity and their biological evaluation.

In this report, we describe the synthesis and biological evaluation of ß(1,3) oligosaccharides that contain an aminoalkyl group and their biological evaluation. A 2,3 diol glycoside with a 4,6 benzylidene protecting group was used as an effective glycosyl acceptor for the synthesis of some ß(1,3) linked glycosides. The use of a combination of a linear tetrasaccharide and a branched pentasaccharide as glycosyl donors led to the preparation of ß(1,3) linear octa- to hexadecasaccharides and branched nona- to heptadecasaccharides in good total yields. Measurements of the competitive effects of the oligosaccharides on the binding of a soluble form of Dectin-1 to a solid-supported Schizophyllan (SPG) revealed that the branched heptadecasaccharide and the linear hexadecasaccharides also have binding activity for Dectin-1. In addition, the two oligosaccharides, both of which contain a ß(1,3) hexadecasaccharide backbone, exhibited agonist activity in a luciferase-assisted NF-κB assay. STD-NMR analyses of complexes of Dectin-1 and the linear hexadecasaccharides clearly indicate Dectin-1 specifically recognizes the sugar part of the oligosaccharides and not the aminoalkyl chain.

ß(1,3) Branched heptadeca- and linear hexadeca-saccharides possessing an aminoalkyl group as a strong ligand to dectin-1.

In this report, we describe the convergent synthesis of ß(1,3) oligosaccharides containing an aminoalkyl group. The branched heptadecasaccharide and linear hexadecasaccharide acted as ligands of dectin-1 whose binding affinity was only 10-fold weaker than that of natural SPG and exhibited dectin-1 agonist activity.

Penile apoptosis in association with p53 under lack of testosterone.

It is known that testosterone deficiency induces apoptosis in the prostate and that p53 protein is involved in this apoptosis. Therefore, p53 protein may also be involved in apoptosis induction in a testosterone-deficient state in the penis. In this study, we investigated whether castration and chemical castration induce apoptosis at penile tissue in rats, and whether p53 protein is involved in this apoptosis. Male SD rats aged 8 weeks were divided into four groups: 1) the Control group; 2) the Castration group; 3) the Estrogen group, in which rats received betaestradiol 17-(beta-D-glucuronide) injection of 500 microg/body/day; and 4) the LH-RH group, in which rats received LH-RH analogue (leuprorelin acetate) injection of 2 mg/kg. The rats were sacrificed after treatment on days 1, 3, 5, 14, and 28 by cervical dislocation. Apoptotic cells and p53 protein-positive cells were observed on the 5th day after treatment and thereafter in all castration, estrogen, and LH-RH groups. These findings showed that both castration and chemical castration induced p53 protein in vascular endothelial cells in the corpus cavernosus during the process of losing testosterone. It was also suggested that in such states, apoptosis is induced in vascular endotherial cells in the corpus cavernosus.