Biomedical subjects

Xin Cong

Publications and source records attributed to Xin Cong.

7 recordsLinked to original sources

PubMed2006

Ring-closing metathesis-based synthesis of (3R,4R,5S)-4-acetylamino-5-amino-3-hydroxy- cyclohex-1-ene-carboxylic acid ethyl ester: a functionalized cycloalkene skeleton of GS4104.

(3R,4R,5S)-4-Acetylamino-5-amino-3-hydroxy-cyclohex-1-ene-carboxylic acid ethyl ester, a functionalized cyclohexene skeleton of GS4104, was diastereoselectively synthesized. A major advantage of this synthesis is the use of readily available L-serine to replace frequently used (-)-shikimic acid or (-)-quinic acid as the starting material. Ring-closing metathesis and diastereoselective Grignard reactions successfully served as the key steps. Absolute configurations of the key intermediates were confirmed by corresponding two-dimensional NMR studies.

Cyclization↗

PubMed2006

Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity.

Huntingtin (Htt) is a large protein of 3144 amino acids, whose function and regulation have not been well defined. Polyglutamine (polyQ) expansion in the N terminus of Htt causes the neurodegenerative disorder Huntington disease (HD). The cytotoxicity of mutant Htt is modulated by proteolytic cleavage with caspases and calpains generating N-terminal polyQ-containing fragments. We hypothesized that phosphorylation of Htt may modulate cleavage and cytotoxicity. In the present study, we have mapped the major phosphorylation sites of Htt using cell culture models (293T and PC12 cells) expressing full-length myc-tagged Htt constructs containing 23Q or 148Q repeats. Purified myc-tagged Htt was subjected to mass spectrometric analysis including matrix-assisted laser desorption/ionization mass spectrometry and nano-HPLC tandem mass spectrometry, used in conjunction with on-target alkaline phosphatase and protease digestions. We have identified more than six novel serine phosphorylation sites within Htt, one of which lies in the proteolytic susceptibility domain. Three of the sites have the consensus sequence for ERK1 phosphorylation, and addition of ERK1 inhibitor blocks phosphorylation at those sites. Other observed phosphorylation sites are possibly substrates for CDK5/CDC2 kinases. Mutation of amino acid Ser-536, which is located in the proteolytic susceptibility domain, to aspartic acid, inhibited calpain cleavage and reduced mutant Htt toxicity. The results presented here represent the first detailed mapping of the phosphorylation sites in full-length Htt. Dissection of phosphorylation modifications in Htt may provide clues to Huntington disease pathogenesis and targets for therapeutic development.

Amino Acid Sequence↗

PubMed2006

Structural relationships in small molecule interactions governing gas-phase enantioselectivity and zwitterionic formation.

Gas-phase zwitterionic amino acids were formed in complexes of underivatized beta-cyclodextrin through reactions with a neutral base, n-propylamine. The reaction was performed in the analyzer cell of an electrospray ionization-Fourier transform mass spectrometer. Most of the natural amino acids were studied with three cyclodextrin hosts including alpha-, beta-, and gamma-cyclodextrin to understand better the structural features that lead to the stabilization of the zwitterionic complexes. Molecular dynamics calculations were performed to provide insight into the structural features of the complexes. The rate constants of the reactions were obtained through kinetic plots. Examination of both L- and D-enantiomers of the amino acid showed that the reaction was enantioselective. The reaction was then employed to analyze mixtures of Glu enantiomers naturally occurring in the bacteria Bacillus licheniformis.

Amino Acids↗

PubMed2005

Chemoselective deprotection of cyclic N,O-aminals using catalytic bismuth(III) bromide in acetonitrile.

Cyclic N,O-aminals can be chemoselectively and efficiently deprotected using a catalytic amount of bismuth(III) bromide in acetonitrile at room temperature. This selectivity was also achieved in the presence of terminal O,O-acetal functionality. The susceptibility of various other groups to cleavage was also investigated. This method has advantages of ease of operation and use of nontoxic and inexpensive reagents in catalytic amounts.

Journal Article↗

PubMed2005

Zwitterion formation in gas-phase cyclodextrin complexes.

Protonated complexes of amino acids and underivatized beta-cyclodextrin, produced by electrospray ionization and trapped in the Fourier transform mass spectrometer, undergo formation of ternary complexes when reacted with alkyl amine. Based on the reactivities of the protonated amino acid complexes with alkylamines, the reactivities of the corresponding amino acid esters, and partially derivatized beta-cyclodextrin hosts, we conclude that the ternary complexes are salt-bridge zwitterionic species composed of amino acid zwitterions and protonated alkylamine all interacting with the hydroxyl groups on the narrow rim of the cyclodextrin. Molecular modeling calculations and experimental results suggest that the interactions of the amino acids with the rims contribute greatly to the formation of the zwitterionic species.

Amino Acids↗

PubMed2004

OBOC small-molecule combinatorial library encoded by halogenated mass-tags.

[reaction: see text] A bromine-/chlorine-containing mass-tag encoding strategy for a small-molecule OBOC combinatorial library is reported. The resulting MALDI FTMS isotope pattern of each tag clearly defines the component building blocks of each "hit" bead in an 1890-member demonstration library screened on-bead for binding against streptavidin via both enzyme-linked colorimetric and Quantum Dot/COPAS assays.

Journal Article↗

PubMed2004

RCM approaches toward the diastereoselective synthesis of vicinal trans-diaminocyclitols from L-serine.

Starting from L-serine, the asymmetric synthesis of four diaminocyclitol derivatives as sugar-based glycosidase inhibitors has been achieved using ring-closing metathesis (RCM) as a key step. Introduction of vicinal trans-diamino functionality onto the acyclic precursors was accomplished by highly diastereoselective addition of Grignard reagent to imine, and the elaboration of polyhydroxylic groups was effected via diastereoselective olefin epoxidation or dihydroxylation. The absolute configurations of final products were confirmed by 2D NMR studies.

Catalysis↗