Synthesis and in vitro evaluation of a phosphonate prodrug: bis ..

Our laboratory reported a convergent method that was used to synthesizephosphatase-stable, cell-permeable peptidomimetic prodrugs targetedto the SH2 domain of STAT3. The key toour synthesis is the use of the fully protected phosphonodifluoromethylcinnamate, 9 (Scheme B). Blocking the phosphonateoxygens with POM groups prior to coupling to 3 preventsunproductive depletion of coupling agent due to the free phosphonategroup in 2. Further, POM groups are typically installedon the silver salts of phosphonates in toluene, which is a poor solventfor peptides and peptidic compounds. In addition to POM protection,the carboxyl group of 9 is derivatized as the pentachlorophenyl(Pcp) ester, a known activator of carboxyl groups. The Pcp ester possessessufficient stability to serve as a protecting group for the POM installationas we described., Our overall yields for the synthesisof the protected phosphotyrosine surrogate 13 were 30–40%, in contrast to 13% for the overall synthesis of 2., This strategy resulted in marked improvements in the synthesis of 1.

and in vitro evaluation of a phosphonate prodrug: ..

Synthesis, anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of ..

"Synthesis and Invitro Evaluation of a Phosphonate Prodrug ..

In conclusion, we have improvedon the synthesis of a novel STAT6inhibitor and show that it potently inhibits the phosphorylation ofSTAT6 in human bronchial epithelial cells stimulated with either IL-4or IL-13. Key to the synthesis is having the phophonate oxygens protectedprior to coupling to the amine. Furthermore, preactivation of thecinnamate building block as pentachlorophenyl ester improved couplingyields compared to the published method. As mentioned, this classof inhibitor has not been evaluated and shown to inhibit STAT6 todate. Given the importance of this transcription factor in asthmaand allergic lung disease, our promising results suggest that targetingthe SH2 domain with phosphatase-stable, cell-permeable phosphopeptidemimetic prodrugs is a potential treatment modality for this disease.

Synthesis and in vitro evaluation of fluorescent and magnetic ..

Because the biological activity has notbeen reported, prodrug 1 was evaluated for its abilityto inhibit STAT6 Tyr641 phosphorylationin intact Beas-2B cells. Compound 1 was added to cellsfrom a DMSO stock solution. Cells were preincubated with 1 for 2 h and were then stimulated with IL-4 or IL-13 for 1 h. Levelsof phospho-STAT6(Y641) and total STAT6 proteins were estimated byWestern blotting of the cell lysates (Figure A). Prodrug 1 inhibited pSTAT6 phosphorylation at 1–10μM in both IL-4 and IL-13 stimulated Beas-2B cells. This resultsuggests that 1 enters cells, the POM groups are cleaved,and the resulting phosphonate binds to the SH2 domain of STAT6 therebypreventing recruitment to the cytokine receptors and subsequent phosphorylationby JAKs. The free phosphate version of 1 was reportedto inhibit the binding of a fluorescently tagged phosphopeptide at Prodrug 1 at concentrations up to 10 μMwas found not to be toxic to Beas-2B cells in a 72 h MTS assay (Figure C). The duration of pSTAT6 inhibition was assayedby treating Beas-2B cells with a single dose of 1 (10 μM). Cellswere incubated for predefined time intervals and were stimulated withIL-4 for 1 h prior to cell lysis. Western blot analysis showed thatnearly complete inhibition of phospho-STAT6(Y641) occurred at 2 hand was maintained up to 48 h (Figure B).The reduction in pSTAT6 was not due to toxicity as the MTS assay showednot effect on proliferation.

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Synthesis of and in vitro and in vivo evaluation of a novel TGF-β1-SF-CS three-dimensional scaffold for bone tissue engineering.

development of prodrugs of phosphonate, ..

Synthesis and in vitro enzymatic and antiviral evaluation of phosphoramidate d4T derivatives ..

Jovem Revela a Matemática Por Trás de Seus 95% de Acertos.

Full text Synthesis, characterization, and in vitro evaluation of curcumin-loade IJN

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs