The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX-2 through an IKKγ/NF-κB-dependent pathway

The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells

Chemical genetics strategies for identification of molecular targets

Chemical genetics is an emerging field that can be used to study the interactions of chemical compounds, including natural products, with proteins. Usually, the identification of molecular targets is the starting point for studying a drug’s mechanism of action and this has been a crucial step in understanding many biological processes. While a great variety of target identification methods have been developed over the last several years, there are still many bioactive compounds whose target proteins have not yet been revealed because no routine protocols can be adopted. This review contains information concerning the most relevant principles of chemical genetics with special emphasis on the different genomic and proteomic approaches used in forward chemical genetics to identify the molecular targets of the bioactive compounds, the advantages and disadvantages of each and a detailed list of successful examples of molecular targets identified with these approaches

New chemistry with old functional groups: On the reaction of isonitriles with carboxylic acids - A route to various amide types

Thermolysis of isonitriles with carboxylic acids provides, in one step, N-formyl imides (see, for example, 8 + 19 → 21). The resultant N-formyl group can be converted to N-H, NCH2OH, or NCH3. This chemistry allows for a new route for synthesizing β-N (asparagine)-linked glycosyl amino acids. Copyright © 2008 American Chemical Society.link_to_subscribed_fulltex

Toward a potential total synthesis of gelsemine: A regioselective hydroboration directed by a remote olefin

Hydroboration of bicyclo[3.2.1]octa-2,6-diene derivatives occurred exclusively on one olefin, and within this olefin, remarkable regioselective addition of boron to one carbon terminus was observed. This regioselectivity was significantly improved with more electrophilic hydroborating agents. The regioselectivity is attributed to the directive effect of a remote olefin.link_to_subscribed_fulltex

Thio FCMA intermediates as strong acyl donors: A general solution to the formation of complex amide bonds

(Chemical Equation Presented) Novel methodology for the formation of amide bonds under neutral conditions is described. Evidence is presented that the active acyl donors are thio FCMA intermediates, generated from the reactions of thioacids with isonitriles. © 2009 American Chemical Society.link_to_subscribed_fulltex

Thio-mediated two-component coupling reaction of carboxylic acids and isonitriles under mild conditions

The coupling reaction between carboxylic acids and isonitriles in the presence of thiophenol as activator under mild conditions is described. © 2009 Elsevier Ltd. All rights reserved.link_to_subscribed_fulltex

Thio-mediated synthesis of derivatized N-linked glycopeptides using isonitrile chemistry

The reaction of oligosaccharide isonitriles with peptide thioacids in the presence of bulky thiophenol as activator to provide N-linked glycopeptides at room temperature is described. © 2009 Elsevier Ltd. All rights reserved.link_to_subscribed_fulltex

Addressing mechanistic issues in the coupling of isonitriles and carboxylic acids: Potential routes to peptidic constructs

Mechanistic issues surrounding the two component coupling (2CC) reaction of carboxylic acids with isonitriles have been investigated. Experimental details suggest the formimidate carboxylate mixed anhydride intermediate exists in both interdictable and noninterdictable form. Furthermore, the 2CC reaction has been applied to the synthesis of a tripeptide featuring two formyl functional groups. Copyright © 2008 American Chemical Society.link_to_subscribed_fulltex

Erratum: Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine (Journal of the American Chemical Society (2002) 124 (9812-9824))

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