RESUMO
Aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) is a bifunctional homodimeric enzyme that catalyzes the last two steps of de novo purine biosynthesis. Homodimerization of ATIC, a protein-protein interaction with an interface of over 5000 Å(2), is required for its aminoimidazole carboxamide ribonucleotide (AICAR) transformylase activity, with the active sites forming at the interface of the interacting proteins. Here, we report the development of a small-molecule inhibitor of AICAR transformylase that functions by preventing the homodimerization of ATIC. The compound is derived from a previously reported cyclic hexapeptide inhibitor of AICAR transformylase (with a K(i) of 17 µM), identified by high-throughput screening. The active motif of the cyclic peptide is identified as an arginine-tyrosine dipeptide, a capped analogue of which inhibits AICAR transformylase with a K(i) value of 84 µM. A library of nonnatural analogues of this dipeptide was designed, synthesized, and assayed. The most potent compound inhibits AICAR transformylase with a K(i) value of 685 nM, a 25-fold improvement in activity from the parent cyclic peptide. The potential for this AICAR transformylase inhibitor in cancer therapy was assessed by studying its effect on the proliferation of a model breast cancer cell line. Using a nonradioactive proliferation assay and live cell imaging, a dose-dependent reduction in cell numbers and cell division rates was observed in cells treated with our ATIC dimerization inhibitor.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores Enzimáticos/farmacologia , Peptídeos Cíclicos/farmacologia , Fosforribosilaminoimidazolcarboxamida Formiltransferase/química , Multimerização Proteica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Contagem de Células , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Células MCF-7 , Estrutura Molecular , Peso Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Fosforribosilaminoimidazolcarboxamida Formiltransferase/antagonistas & inibidores , Fosforribosilaminoimidazolcarboxamida Formiltransferase/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis of the subgroups of acetogenins containing non-adjacent bis-THF and non-adjacent THF-THP core units is reviewed. Specifically, total syntheses of gigantecin, 4-deoxygigantecin, cis-sylvaticin, squamostatin-C, squamostatin-D, sylvaticin and mucocin are discussed.
Assuntos
Acetogeninas/classificação , Acetogeninas/síntese química , Furanos/síntese química , Piranos/síntese química , Acetogeninas/química , Furanos/química , Lactonas/síntese química , Lactonas/química , Espectroscopia de Ressonância Magnética , Piranos/químicaRESUMO
An asymmetric total synthesis of (+)-cis-sylvaticin is described. Key steps include the use of permanganate-mediated oxidative cyclization of 1,5-dienes to synthesize the two major fragments 2 and 3 and a catalytically efficient tethered RCM to unite these THF-containing fragments. In addition, t-BuP 4 base was found to reliably promote rapid alkylation of the butenolide precursor fragment 4.