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Jiqing Jiang

Publications and source records attributed to Jiqing Jiang.

9 recordsLinked to original sources
PubMed2006

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

Animals↗
PubMed2003

Antibiotic optimization via in vitro glycorandomization.

In nature, the attachment of sugars to small molecules is often used to mediate targeting, mechanism of action and/or pharmacology. As an alternative to pathway engineering or total synthesis, we report a useful method, in vitro glycorandomization (IVG), to diversify the glycosylation patterns of complex natural products. We have used flexible glycosyltransferases on nucleotide diphosphosugar (NDP-sugar) libraries to generate glycorandomized natural products and then applied chemoselective ligation to produce monoglycosylated vancomycins that rival vancomycin.

Anti-Bacterial Agents↗
PubMed2003

Studies on the substrate specificity of Escherichia coli galactokinase.

In vitro glycorandomization (IVG) technology is dependent upon the ability to rapidly synthesize sugar phosphates. Compared with chemical synthesis, enzymatic (kinase) routes to sugar phosphates would be attractive for this application. This work focuses upon the development of a high-throughput colorimetric galactokinase (GalK) assay and its application toward probing the substrate specificity and kinetic parameters of Escherichia coli GalK. The demonstrated dinitrosalicylic assay should also be generally applicable to a variety of sugar-processing enzymes. [reaction: see text]

Colorimetry↗
PubMed2003

Substrate specificity of NovM: implications for novobiocin biosynthesis and glycorandomization.

[reaction: see text] In an effort to expand the scope of natural product in vitro glycorandomization (IVG), the substrate specificity of NovM was investigated. A test of four aglycon analogues and over 40 nucleotide sugars revealed NovM has a surprisingly stringent substrate specificity and provided only three new "unnatural" natural products. On the basis of the determined substrate specificity, an alternative to the sugar nucleotide biosynthetic dogma and a cautionary note for the general applicability of IVG are introduced.

Anti-Bacterial Agents↗
PubMed2003

Aromatic nucleophilic substitution or CuI-catalyzed coupling route to martinellic acid.

Condensation of beta-amino ester 8b with triflate 7 gives N-aryl amino ester 11, which is converted into 2-substituted 4-oxoquinoline 4 using an intramolecular Dieckmann reaction as the key step. CuI-mediated coupling of beta-amino ester 8a with 1,4-diiodobenzene followed by an intramolecular acylation and Pd-catalyzed carbonylation provide another manner to 4. Alkylation of 4 and subsequent reductive amination deliver the cyclic imine 14, which is transformed into triamine 3 by ordinary operations. Guanylation of 3 under mild condition followed by deprotection results in the synthesis of martinellic acid 1.

Alkaloids↗
PubMed2002

Expanding pyrimidine diphosphosugar libraries via structure-based nucleotidylyltransferase engineering.

In vitro "glycorandomization" is a chemoenzymatic approach for generating diverse libraries of glycosylated biomolecules based on natural product scaffolds. This technology makes use of engineered variants of specific enzymes affecting metabolite glycosylation, particularly nucleotidylyltransferases and glycosyltransferases. To expand the repertoire of UDP/dTDP sugars readily available for glycorandomization, we now report a structure-based engineering approach to increase the diversity of alpha-d-hexopyranosyl phosphates accepted by Salmonella enterica LT2 alpha-d-glucopyranosyl phosphate thymidylyltransferase (E(p)). This article highlights the design rationale, determined substrate specificity, and structural elucidation of three "designed" mutations, illustrating both the success and unexpected outcomes from this type of approach. In addition, a single amino acid substitution in the substrate-binding pocket (L89T) was found to significantly increase the set of alpha-d-hexopyranosyl phosphates accepted by E(p) to include alpha-d-allo-, alpha-d-altro-, and alpha-d-talopyranosyl phosphate. In aggregate, our results provide valuable blueprints for altering nucleotidylyltransferase specificity by design, which is the first step toward in vitro glycorandomization.

Amino Acid Substitution↗
PubMed2002

Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides.

Analogs of the glycopeptide antibiotics vancomycin and teicoplanin with alterations in one or both sugar moieties of the disaccharide have been prepared by tandem action of the vancomycin pathway glycosyltransferases GtfE and GtfD. All four regioisomers (2-, 3-, 4-, 6-) of TDP-deoxyglucoses and UDP/TDP-aminoglucoses were prepared, predominantly by action of D-glucopyranosyl-1-phosphate thymidylyltransferase, E(p). GtfE transferred the deoxyglucoses or aminoglucoses onto the 4-OH of 4-hydroxyphenylglycine of both the vancomycin and teicoplanin aglycone scaffolds. Kinetic analysis indicated the 2-, 3-, 4-, and 6-amino-glucoses were transferred by GtfE with only a 4- to 30-fold drop in k(cat) and no effect on K(m) compared to the native substrate, UDP/TDP-glucose, suggesting preparative utility. The next enzyme, GtfD, could utilize the variant glucosyl-peptides as substrates for transfer of L-4-epi-vancosamine. The aminosugar moieties in these variant glycopeptides introduce sites for acylation or reductive alkylation.

Anti-Bacterial Agents↗
PubMed2001

Expanding the Pyrimidine Diphosphosugar Repertoire: The Chemoenzymatic Synthesis of Amino- and Acetamidoglucopyranosyl Derivatives This contribution was supported by the National Institutes of Health (GM58196 and CA84374), a Cancer Center Support Grant (CA-08748), and a grant from the Special Projects Committee of the Society of Memorial Sloan-Kettering Cancer Center. J.S.T. is an Alfred P. Sloan Research Fellow and a Rita Allen Foundation Scholar.

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Journal Article↗