RESUMO
An efficient three-step construction of the highly oxygenated D-ring of the kinamycin antibiotics is reported for a simple model system. A comparison of the spectroscopic characteristics of the synthetic models with those of natural kinamycin F, which is suspected to be the bioactive form of the kinamycins, leads to the conclusion that the favored D-ring conformation of kinamycin F differs from that of the other partially or fully acylated variants.
Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Quinonas/síntese química , Quinonas/química , Streptomyces/químicaRESUMO
A general and efficient synthesis of 5-aryl imidazo[1,5- a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5- a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH2, NMe2, and OMe, as well as 8-aryl derivatives, X = Ar'. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.
Assuntos
Hidrocarbonetos Bromados/química , Imidazóis/síntese química , Paládio/química , Pirazinas/síntese química , Catálise , Técnicas de Química Combinatória , Imidazóis/química , Estrutura Molecular , Pirazinas/química , EstereoisomerismoRESUMO
This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.
RESUMO
The cell growth and cell cycle inhibitory properties of the bacterial metabolites kinamycin A and kinamycin C were investigated in an attempt to determine their mechanism of action and to develop these or their analogs as anticancer agents. Both kinamycin A and kinamycin C have a highly unusual and potentially reactive diazo group. Even with short incubations, both the kinamycins were shown to have very potent cell growth inhibitory effects on either Chinese hamster ovary or K562 cells. Kinamycin C induced a rapid apoptotic response in K562 cells. The cell cycle analysis results in synchronized Chinese hamster ovary cells treated with kinamycin A revealed that they only displayed a G1/S phase block upon entry to the second cycle. Both kinamycins inhibited the catalytic decatenation activity of DNA topoisomerase IIalpha, but neither kinamycin acted as a topoisomerase II poison. Their inhibition of catalytic activity was not correlated with cell growth inhibitory effects. Pretreatment of the kinamycins with dithiothreitol protected the topoisomerase IIalpha activity, which suggested that they may be targeting critical protein sulfhydryl groups, either through reaction with the quinone or with an activated electrophilic diazo group. Neither kinamycin A nor kinamycin C intercalated into DNA, nor were they able to cross-link DNA. Although the cellular target(s) of the kinamycins has yet to be identified, the cluster map analysis, and the cell cycle and proapoptotic effects suggest that kinamycin C has a target different than other established anticancer compounds.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Compostos Azo/farmacologia , Ciclo Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antibióticos Antineoplásicos/química , Antígenos de Neoplasias/metabolismo , Compostos Azo/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Análise por Conglomerados , Cricetinae , Reagentes de Ligações Cruzadas , DNA Girase/metabolismo , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/genética , DNA Super-Helicoidal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/enzimologia , Humanos , Células K562 , NAD/metabolismo , Naftoquinonas/química , Plasmídeos/genética , Quinonas/química , Quinonas/farmacologia , Inibidores da Topoisomerase IIRESUMO
Theoretical and chemical studies of the reactivity of isoprekinamycin, the kinamycins, and the lomaiviticins support the proposal that these natural products exhibit enhanced diazonium salt character and may owe their antitumor antibiotic properties to their ability to act as electrophilic azo-coupling agents in vivo.