Synthesis of Phosphatase-Stable, Cell-Permeable Peptidomimetic Prodrugs That Target the SH2 Domain of Stat3

Abstract

The synthesis of prodrugs targeted to the SH2 domain of Stat3 is reported. Using a convergent strategy, the pivaloyloxymethyl phosphonodiester of pentachlorophenyl 4-phosphonodifluoromethylcinnamate, a phosphotyrosine surrogate, was synthesized and used to acylate peptidomimetic fragments that were prepared on solid supports. Two prodrugs described here inhibited the phosphorylation of Stat3 in breast tumor cells.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…In this case, a xenograft experiment was performed to assess activity in a MDA-MB-468 tumor model, and a ~30% decrease in tumor volume was observed after four weeks of treatment [227]. In contrast to the earlier findings [223], in this study the bis-POM compound 101 , prepared as a phosphotyrosine surrogate, is significantly more effective than the mono-POM analog at producing cellular activity [228]. Subsequent studies therefore relied on the bis-POM approach to identify inhibitors of Stat3 [229,230] and Stat6 [231] binding interactions.…”

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…Synthesis of the STAT6 antagonist PM-242H was based on previously published methods [37,38] . The reaction was monitored by HPLC.…”

Targeting Sh2 Domains in Breast Cancer

“…To prepare these phosphopeptide mimetics for cellular studies, the phosphate group was replaced with the phosphatase-stable phosphonodifluoromethyl group [97,102]. To block the negative charges of the phosphonate and allow cell penetration, the oxygens were capped with carboxyesterase-labile pivaloyloxymethyl groups [97,102].…”

“…To block the negative charges of the phosphonate and allow cell penetration, the oxygens were capped with carboxyesterase-labile pivaloyloxymethyl groups [97,102]. Cellular potency was influenced by structural features that had little or opposite effects on affinity for the protein [97,100].…”