RESUMEN
The covalent functionalization of multi-walled carbon nanotubes (MWCNTs) with a proline-based derivative is reported. Initially, MWCNTs were oxidized in order to introduce a large number of carboxylic units on their tips followed by N-tert-butoxycarbonyl-2,2'(ethylenedioxy)bis-(ethylamine) conjugation through an amide bond. Then, a proline derivative bearing a carboxylic terminal moiety at the 4-position was coupled furnishing proline-modified MWCNTs. This new hybrid material was fully characterized by spectroscopic and microscopy means and its catalytic activity in the asymmetric aldol reaction between acetone and 4-nitrobenzaldehyde was evaluated for the first time, showing to proceed almost quantitatively in aqueous media. Furthermore, several amino-modified MWCNTs were prepared and examined in the particular aldol reaction. These new hybrid materials exhibited an enhanced catalytic activity in water, contrasting with the pristine MWCNTs as well as the parent organic molecule, which failed to catalyze the reaction efficiently. Furthermore, the modified MWCNTs proved to catalyze the aldol reaction even after three repetitive cycles. Overall, a green approach for the aldol reaction is presented, where water can be employed as the solvent and modified MWCNTs can be used as catalysts, which can be successfully recovered and reused, while their catalytic activity is retained.
RESUMEN
This work presents a thorough investigation of the interaction of the novel synthetic pyrrolidinone analog MMK3 with the model membrane system of dipalmitoylphosphatidylcholine (DPPC) and the receptor active site. MMK3 has been designed to exert antihypertensive activity by functioning as an antagonist of the angiotensin II receptor of subtype 1 (AT(1)). Its low energy conformers were characterized by 2D rotating-frame Overhauser effect spectroscopy (ROESY) in combination with molecular dynamics (MD) simulations. Docking study of MMK3 shows that it fits to the AT(1) receptor as SARTANs, however, its biological activity appears to be lower. Thus, differential scanning calorimetry (DSC), Raman spectroscopy and small angle X-ray scattering (SAXS) experiments on the interaction of MMK3 with DPPC bilayers were carried out and results demonstrate that the drug is well incorporated into the membrane leaflets and furthermore causes partial bilayer interdigitation, although less effective than SARTANs. Thus, it appears that the nature of the bilayer matrix and the stereoelectronic active site requirements of the receptor are responsible for the low bioactivity of MMK3.
Asunto(s)
Imidazoles/metabolismo , Membrana Dobles de Lípidos/metabolismo , Pirrolidinas/metabolismo , Pirrolidinonas/química , Receptores de Angiotensina/metabolismo , 1,2-Dipalmitoilfosfatidilcolina , Rastreo Diferencial de Calorimetría , Imidazoles/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Estructura Secundaria de Proteína , Protones , Pirrolidinas/química , Espectrometría Raman , Temperatura , Difracción de Rayos XRESUMEN
AT(1) antagonists (SARTANs) constitute the last generation of drugs for the treatment of hypertension, designed and synthesized to mimic the C-terminal segment of the vasoconstrictive hormone angiotensin II (AngII). They exert their action by blocking the binding of AngII on the AT(1) receptor. Up to date eight AT(1) antagonists have been approved for the regulation of high blood pressure. Although these molecules share common structural features and are designed to act under the same mechanism, they have differences in their pharmacological profiles and antihypertensive efficacy. Thus, there is still a need for novel analogues with better pharmacological and financial profiles. An example of a novel synthetic non peptide AT(1) antagonist which devoids the classical template of SARTANs is MM1. In vivo studies showed that MMK molecules, which fall in the same class of MM1, had a significant antihypertensive (40-80% compared to the drug losartan) activity. However, in vitro affinity studies showed that losartan has considerably higher affinity. The theoretical docking studies showed that MM1 acts on the same site of the receptor as losartan. They exert hydrophobic interactions with amino acid Val108 of the third helix of the AT(1) receptor and other hydrophobic amino acids in spatial vicinity. In addition, losartan favours multiple hydrogen bondings between its tetrazole group with Lys199. These additional interactions may in part explain its higher in vitro binding affinity.