RESUMEN
Here we describe the leishmanicidal activities of a library of 2,6,9-trisubstituted purines that were screened for interaction with Cdc2-related protein kinase 3 (CRK3) and subsequently for activity against parasitic Leishmania species. The most active compound inhibited recombinant CRK3 with an IC50 value of 162 nM and was active against Leishmania major and Leishmania donovani at low micromolar concentrations in vitro. Its mode of binding to CRK3 was investigated by molecular docking using a homology model.
Asunto(s)
Leishmania donovani/efectos de los fármacos , Leishmania major/efectos de los fármacos , Proteínas Proto-Oncogénicas c-crk/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Sitios de Unión , Modelos Moleculares , Estructura Molecular , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
The platinum(II) dichlorido and oxalato complexes of the general formula cis-[PtCl(2)(nHaza)(2)] (1-3) [Pt(ox)(nHaza)(2)] (4-6) involving 7-azaindole halogeno-derivatives (nHaza) were prepared and thoroughly characterized. A single-crystal X-ray analysis of cis-[PtCl(2)(3ClHaza)(2)]·DMF (1·DMF; 3ClHaza symbolizes 3-chloro-7-azaindole) revealed a distorted square-planar arrangement with both the 3ClHaza molecules coordinated through their N7 atoms in a cis fashion. In vitro cytotoxicity of the complexes was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay against the HOS (osteosarcoma), MCF7 (breast adenocarcinoma) and LNCaP (prostate adenocarcinoma) human cancer cell lines. The dichlorido complexes 1-3 (IC(50)=3.8, 3.9, and 2.5 µM, respectively) showed significantly higher in vitro anticancer effect against HOS as compared with cisplatin, whose IC(50)=37.7 µM. The biological effect of cisplatin against MCF7 (IC(50)=24.5 µM) and LNCaP (IC(50)=3.8 µM) was also exceeded by 1-3 (except for 2 against LNCaP), but the difference can be classified as significant only in the case of 1 (IC(50)=3.4 µM) and 3 (IC(50)=2.0 µM) against MCF7. The molecular pharmacological studies (RNA synthesis by T7 RNA polymerase in vitro) proved that 1-3 bind to DNA in a similar manner as cisplatin, since the RNA synthesis products of 1-3 and cisplatin showed a similar sequence profile of major bands.