RESUMEN
The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Depsipéptidos/síntesis química , Depsipéptidos/farmacología , Factores de Transcripción E2F/metabolismo , Factores de Transcripción/antagonistas & inhibidores , beta Catenina/antagonistas & inhibidores , Antineoplásicos/química , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Depsipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Factor de Transcripción E2F1/metabolismo , Humanos , Concentración 50 Inhibidora , Factor de Transcripción 4RESUMEN
A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.
Asunto(s)
Antineoplásicos/síntesis química , Macrólidos/síntesis química , Antineoplásicos/química , Brioestatinas , Macrólidos/química , EstereoisomerismoRESUMEN
Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones.