RESUMEN
A series of novel distamycin-related polyanionic compounds were compared for their anti-HIV activity. Several were highly potent inhibitors of HIV virus-induced cell killing and viral replication of a wide variety of laboratory isolates, as well as a monocytotropic virus and a clinical isolate in human peripheral blood lymphocytes. These compounds are structurally different from other sulfonic acid containing compounds reported to be potent inhibitors of the human immunodeficiency virus (HIV) in two respects: (1) they are structurally related to the non-toxic minor groove DNA binder distamycin; and (2) a number of them contain the aromatic phosphonic acid group. The compounds that were evaluated can be categorized into monomeric or dimeric ureido structural classes incorporating the bisamido-N-methylpyrrolenaphthalene-sulfonic acid group, with differences in the number and position of the sulfonic acids on the naphthalene rings. Broader structure-activity studies were made possible through the synthesis and evaluation of the compounds containing only a single N-methylpyrrole unit, those incorporating the N-methylpyrazole structure, and compounds having the isosteric phosphonic acid group substituted for the sulfonic acid group. One of the most potent of the inhibitors was 2,2'[4,4'[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide- 1,1'-dimethyl]]-4,6,8 naphthalenetrisulfonic acid] hexasodium salt, NSC 651015. This compound, the phosphonic acid analog NSC 662162, and the monomeric compound NSC 651018 were studied to determine the mechanism of their inhibitory activity. Mechanistic studies revealed that inhibition was due to the disruption of virus attachment to CD(4+)-susceptible cells and a further restraint on fusion of virus and cell membranes. The relative tolerance of these compounds in mice suggests that sufficient antiviral concentrations could be reached in vivo and thus may prove valuable in the treatment of AIDS patients.
Asunto(s)
Antivirales/farmacología , Distamicinas/farmacología , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Antivirales/química , Línea Celular , Distamicinas/química , VIH-1/fisiología , VIH-2/fisiología , Humanos , Ratones , Datos de Secuencia Molecular , Relación Estructura-Actividad , Azufre , Replicación Viral/efectos de los fármacosRESUMEN
Sulfonated distamycin (Suradista) derivatives exhibit anti-HIV-1 activity by inhibiting the binding of the viral envelope glycoprotein gp120 to its receptor (CD4). With the aim to propose a possible binding mode between Suradistas and the CD4 macromolecule, molecular docking experiments, followed by energy minimization of the complexes thus obtained, were performed. Computational results show that ligand binding at the CD4 surface involves two or three positively charged regions of the macromolecule, in agreement with the results of X-ray crystallographic analysis of a ternary complex (CD4/gp120/neutralizing antibody) recently reported in the literature. Our findings account well for the structure-activity relationship found for Suradista compounds.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Antígenos CD4/metabolismo , Fármacos Anti-VIH/farmacología , Sitios de Unión , Antígenos CD4/química , Antígenos CD4/efectos de los fármacos , Simulación por Computador , Distamicinas/química , Distamicinas/metabolismo , Distamicinas/farmacología , Diseño de Fármacos , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Conformación MolecularRESUMEN
The design, synthesis, and biological evaluation of a series of pyrrole and pyrazole congeners 2 of suramin, directed toward the development and identification of new ligands that complex the human fibroblast growth factor (bFGF), thereby inhibiting tumor-promoted angiogenesis, is reported. Compounds 2 were evaluated for their ability to inhibit binding of bFGF to its receptor, in vivo bFGF-induced angiogenesis, and neovascularization of the chorioallantoic membrane in comparison with suramin. These assays showed that ligands 2 exhibit moderate to good activity, comparable to that of suramin, and are less toxic than suramin itself. In this study, affinity data of ligands in combination with the crystal structure of bFGF were used to explain structure-affinity relationships and to gain an insight into the possible mode of ligand-protein interaction. Due to the lack of experimental structural data on the ligand-bFGF complexes, molecular mechanics techniques were used to obtain putative bioactive conformations and to generate docked complexes with the three-dimensional structure of bFGF. These experiments led to suggest that compounds 2 give rise to 1:1 complexes with bFGF through an unprecedented, bidentate attachment of their naphthylsulfonate groups to two main domains, commonly referred to as the heparin binding site and the receptor binding site, on bFGF, thus preventing the interaction of the growth factor with its receptor.