RESUMO
Several recent studies of hydroxyl-functionalized ionic liquids (ILs) have shown that cation-cation interactions can be dominating these materials at the molecular level when the anion involved is weakly interacting. The hydrogen bonds between the like ions led to the formation of interesting chain-like, ring-like, or distinct dimeric (i. e. two ion pairs) supermolecular clusters. In the present work, vibrational spectroscopy (ATR-IR and Raman) and density functional theory (DFT) calculations of the hydroxyl-functionalized imidazolium ionic liquid C2 OHmimCl indicate that anion-cation hydrogen bonding interactions are dominating, leading to the formation of distinct dimeric ion pair clusters. In this arrangement, the Cl- anions function as a bridge between the cations by establishing bifurcated hydrogen bonds with the OH group of one cation and the C(2)-H of another cation. Cation-cation interactions, on the other hand, do not play a significant role in the observed clusters.
RESUMO
We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimer's disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimer's disease (AD) and in diseases involving abnormal pre-mRNA splicing.
Assuntos
Processamento Alternativo/efeitos dos fármacos , Benzodioxóis/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Imidazolinas/síntese química , Poríferos/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Precursores de RNA/genética , Animais , Organismos Aquáticos , Benzodioxóis/química , Benzodioxóis/farmacologia , Cristalografia por Raios X , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Imidazolinas/química , Imidazolinas/farmacologia , Microvasos/citologia , Modelos Moleculares , Proteínas Nucleares/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Relação Quantitativa Estrutura-Atividade , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina , Estereoisomerismo , Quinases DyrkRESUMO
New derivatives of the marine alkaloid leucettamine B were prepared in five steps with overall yields ranging from 23 to 30%. The key step of our strategy has been the sulfur/nitrogen displacement under solvent-free microwave irradiation of (5Z) 5-benzo[1,3]-dioxo-5-ylmethylene-2-ethylsulfanyl-3,5-dihydroimidazol-4-one 3 with a mono-protected ethylenediamine 2. After deprotection of the N-Boc group, the amino derivative of leucettamine B 5 was subjected to reductive amination in two steps with retention of configuration of the double bond, to lead to eight new analogs of leucettamine B. The effect of these compounds on CK1alpha/beta, CDK5/p25, and GSK-3alpha/beta were investigated.
