RESUMO
Speciation is characterized by the development of reproductive isolating barriers between diverging groups. A seminal paper of a mathematical model of speciation was published by Orr (1995), extended by Livingstone et al. (2012) to incorporate interaction networks. Here, we further develop the model to take into account the possibility of different substitution rates for network nodes of different connectivity. Mathematically, this amounts to sampling nodes from an undirected graph where the inclusion probability for a given node depends on its degree (number of connecting edges). We establish formulas for the rate of speciation and identify a crucial parameter that is a measure of the deviation from simple random sampling.
Assuntos
Especiação Genética , Modelos Genéticos , Domínios e Motivos de Interação entre ProteínasRESUMO
A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (< 50 nM) and cellularly < or = 100 nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indóis/química , Ureia/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Humanos , Indóis/farmacologia , Camundongos , Células NIH 3T3 , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.
Assuntos
Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Histona Desacetilases , Cetonas/farmacologia , Inibidores Enzimáticos/química , Cetonas/química , Cinética , Relação Estrutura-AtividadeRESUMO
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
