N-methyl-O-benzylhydroxylamine derivatives of sialylated oligosaccharides, their synthesis and separation with reversed-phase HPLC.

The human milk trisaccharide 3'- sialyllactose was reacted with an excess of N-methyl-O-benzylhydroxylamine (MBHA) and the product 3'- sialyllactose-MBHA was isolated in high (91%) yield by solid-phase extraction. The isomeric trisaccharide 6'-sialyllactose-MBHA was also prepared, in this case by enzymatic sialylation of lactose-MBHA. A 50/50 mixture of the two sialyllactose-MBHA derivatives was easily separated by reversed-phase HPLC.

Derivatization of sugars with N,O-dimethylhydroxylamine. Efficient RP-HPLC separation of sugar mixtures.

Sugars were derivatized with N,O-dimethylhydroxylamine (DMHA) using a simple procedure. The disaccharides lactose and chitobiose and the human milk tetrasaccharides lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) were used as examples. The β-glycosylamines were formed exclusively in good yields (80-84%).

Reversible derivatization of sugars with carbobenzyloxy groups and use of the derivatives in solution-phase enzymatic oligosaccharide synthesis.

Simple protocols for attaching and detaching carbobenzyloxy (Cbz) groups at the reducing end of sugars was developed. Briefly, lactose was converted into its glycosylamine, which was then acylated with carbobenzyloxy chloride in high overall yield. The obtained lactose Cbz derivative was used in sequential glycosylations using glycosyltransferases and nucleotide sugars in aqueous buffers.

Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms.

An oestrogen receptor β-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma.

Background: Cholangiocarcinoma cells over-express oestrogen receptor-β, which displays anti-proliferative and pro-apoptotic effects.

Aim: To evaluate the effects of a newly developed and highly selective oestrogen receptor-β agonist (KB9520) on experimental intrahepatic cholangiocarcinoma.

Methods: In vitro, the effects of KB9520 on apoptosis and proliferation of HuH-28 cells, HuH-28 cells with selective oestrogen receptor-β silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-α and oestrogen receptor-β negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-α) were evaluated.

Design and synthesis of 2'-anilino-4,4'-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3.

The design and synthesis of a new series of c-Jun N-terminal kinase-3 (JNK3) inhibitors with selectivity against JNK1 are reported. The novel series of substituted 2'-anilino-4,4'-bipyridines were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of compounds crystallized into the JNK3 ATP binding active site.

Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3.

The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site.