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Biomedical subjects

Zhitao Li

Publications and source records attributed to Zhitao Li.

7 recordsLinked to original sources
PubMed2006

Mechanistic studies and methods to prevent aglycon transfer of thioglycosides.

Thioglycosides have been employed extensively for the synthesis of complex oligosaccharides, carbohydrate libraries, and mimetics of O-glycosides. While very useful, aglycon transfer is a problematic side reaction with thioglycosides. In this paper, a series of mechanistic studies are described. The aglycon transfer process is shown to affect both armed and disarmed thioglycosides, cause anomerization of the carbon-sulfur bond of a thioglycoside, and destroy the product of a glycosylation reaction. The results indicate that the aglycon transfer process can be a major problem for a wide range of thioglycosides. This side reaction is especially important to consider when carrying out complex reactions such as solid-phase glycosylations, one-pot or orthogonal multicomponent glycosylations, and construction of carbohydrate libraries. To prevent transfer, a number of modified aglycons were examined. The 2,6-dimethylphenyl (DMP) aglycon was found to effectively block transfer in a variety of model studies and glycosylation reactions. The DMP group can be installed in one step from a commercially available thiol (2,6-dimethylthiophenol) and is useable as a glycosyl donor. On the basis of these features, the DMP group is proposed as a convenient and improved aglycon for thioglycosides.

Energy Transfer↗
PubMed2005

Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s).

The principle of methyl scanning is proposed for determination of the sites of interaction between biologically active small molecules and their macromolecular target(s). It involves the systematic preparation of a family of methylated derivatives of a compound and their biological testing. As a functional assay, the method can identify the regions of a molecule that are important (and unimportant) for biological activity against even unknown targets, and thus provides an excellent complement to structural biology. Methyl scanning was applied to demethylasterriquinone B1, a small-molecule mimetic of insulin. A new, optimal total synthesis of this natural product was developed that enables the family of methyl scan derivatives to be concisely prepared for evaluation in a cellular assay. The results of this experiment were used to design a biotin-demethylasterriquinone conjugate for use as an affinity reagent. This compound was prepared in tens of milligram quantities in a four-step synthesis.

Animals↗
PubMed2005

Carbohydrate array analysis of anti-Tn antibodies and lectins reveals unexpected specificities: implications for diagnostic and vaccine development.

The Tn antigen is a carbohydrate antigen expressed in most carcinomas, during embryogenesis, on pathogenic parasites, and on HIV. It has been evaluated extensively as a potential diagnostic marker and several Tn-based vaccines are in clinical trials. Based on discrepancies in the literature regarding Tn expression, we began to question whether antibodies and lectins used routinely to detect the Tn antigen were providing accurate information. To investigate this possibility, a carbohydrate microarray and a highly sensitive assay were developed and three frequently used Tn receptors (HBTn1, Bric111, and VVL-B4) were evaluated. Carbohydrate-array analysis revealed unexpected cross-reactivity with other human carbohydrate epitopes. VVL-B4 bound the Tn antigen, GalNAcalpha1-6Gal, and GalNAcalpha1-3Gal. Bric111 bound the Tn antigen, blood group A, GalNAcalpha1-6Gal, and GalNAcalpha1-3Gal. HBTn1 showed the best selectivity, but still displayed moderate binding to blood group A. Implications for the development of Tn-based diagnostics and vaccines are discussed.

Antibodies↗
PubMed2003

Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones.

Overexpression of the Cdc25A and Cdc25B dual-specificity phosphatases correlates with a wide variety of cancers, making the Cdc25s attractive drug targets for anticancer therapies. However, the search for good lead molecules has been hampered by the reactivity of the active site thiolate anion and the flat solvent-exposed active site region. We describe here the indolyldihydroxyquinones, a new class of inhibitors of Cdc25 that bind reversibly to the active site with submicromolar potency. Structure-activity relationships in the 50 derivatives of the lead molecule 2,5-dihydroxy-3-(1H-indol-3-yl)[1,4]benzoquinone show interesting and consistent trends identifying features required for inhibition of all three isoforms of Cdc25. The compounds do not show time-dependent inhibition, indicating that they form neither covalent adducts with nor oxidize the active site thiol. Our best compounds, 2,5-dihydroxy-3-(7-farnesyl-1H-indol-3-yl)[1,4]benzoquinone and 2,5-dihydroxy-3-(4,6-dichloro-7-farnesyl-1H-indol-3-yl)[1,4]benzoquinone, are competitive with substrate for the active site and yield K(i)s of 640 and 470 nM, respectively. Binding of the indolylhydroxyquinones is diminished by three, but not by six other, specific mutations in the active site region. Additionally, the flexible C-terminal tail required for binding of protein substrate is also required for binding derivatives with hydrophobic modifications at the 7-position. The indolyldihydroxyquinones compete effectively with the protein substrate for Cdc25 in vitro and lead to rapid cell death in vivo. Thus, the indolyldihydroxyquinones will serve as useful lead molecules for drug discovery and further cell-based studies on the role of Cdc25s in cell cycle control.

Binding Sites↗
PubMed2002

Synthesis of 2,5-dihydroxy-3-(indol-3-yl)benzoquinones by acid-catalyzed condensation of indoles with 2,5-dichlorobenzoquinone.

Three methods for the conjugate addition of indoles to 2,5-dichlorobenzoquinone have been developed. A wide variety of indoles substituted with halogen, alkyl, alkoxy, and aryl groups participate in anaerobic condensation reactions promoted by HCl, H2SO4, or CH3CO2H. The hydroquinone product is partially oxidized by excess dichlorobenzoquinone and fully converted to the 2,5-dichloro-3-(indol-3-yl)benzoquinone targets by DDQ or Ag2CO3 oxidation. 2,5-Dihydroxy-3-(indol-3-yl)benzoquinones can be obtained from the dichlorides by alkaline hydrolysis. The rotational characteristics of the biaryl bond created in these reactions have been examined by theoretical and spectroscopic methods.

Journal Article↗
PubMed2002

Total syntheses of demethylasterriquinone B1, an orally active insulin mimetic, and demethylasterriquinone A1.

Two total syntheses of the unsymmetrical bis-indolylquinone natural product demethylasterriquinone B1 (also known as L-783,281) have been accomplished. The first exploits a known base-promoted condensation of indoles with bromanil, which stops at monoaddition using the sterically hindered 2-isoprenylindole. This permits addition of the second indole, 7-prenylindole, which gives both meta- and para-substituted bis-indolylquinone products. This regiochemical control problem was solved by extension of a method we recently developed for acid-promoted addition of indoles to 2,5-dichlorobenzoquinone. Under our original mineral acid conditions, reaction of 2-isoprenylindole with dichlorobenzoquinone fails, but it succeeds with 3-bromo-2,5-dichlorobenzoquinone using acetic acid as the promoter. The regiochemistry established in such selectively bromine-substituted quinones can be exploited in Stille couplings. As a model system, the synthesis of demethylasterriquinone A1 was accomplished using as the key step a Stille coupling of a 2,5-dibromobenzoquinone with an (N-isoprenylindol-3-yl)tin, producing the para-substituted bis-indolylquinone exclusively. Use of a (7-prenylindole)tin in coupling with a bromo-2,5-dichloro-4-indolylbenzoquinone gives the demethylasterriquinone B1 precursor. The dihaloquinone products of these indole/quinone coupling processes can be hydrolyzed to the dihydroxyquinone natural products. Demethylasterriquinone B1 is of high recent interest as a small molecule insulin mimetic with oral anti-diabetic activity in mice.

Aspergillus↗