RESUMEN
A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a-17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81-9.03 × 104 M-1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a-17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a-17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7-GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR-GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e-17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.
Asunto(s)
Antineoplásicos , Citostáticos , ADN-Topoisomerasas de Tipo I/metabolismo , Simulación del Acoplamiento Molecular , Acridinas/farmacología , Acridinas/química , Citostáticos/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Dicroismo Circular , Antineoplásicos/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC50 value ranging from 0.82 to 0.91⯵M against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC50 values of 0.33 and 0.23⯵M, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.
Asunto(s)
Apoptosis/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/efectos de los fármacos , Metilaminas/síntesis química , Simulación del Acoplamiento Molecular/métodos , Humanos , Metilaminas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
In this paper novel isoindolines substituted with cyano and amidino benzimidazoles and benzothiazoles were synthesized as new potential anti-cancer agents. The new structures were evaluated for antiproliferative activity, cell cycle changes, cell death, as well as DNA binding and topoisomerase inhibition properties on selected compounds. Results showed that all tested compounds exerted antitumor activity, especially amidinobenzothiazole and amidinobenzimidazole substituted isoindolin-1-ones and benzimidazole substituted 1-iminoisoindoline that showed antiproliferative effect in the submicromolar range. Moreover, the DNA-binding properties of selected compounds were evaluated by biophysical and biochemical approaches including thermal denaturation studies, circular dichroism spectra analyses and topoisomerase I/II inhibition assays and results identified some of them as strong DNA ligands, harboring or not additional topoisomerase II inhibition and able to locate in the nucleus as determined by fluorescence microscopy. In conclusion, we evidenced novel cyano- and amidino-substituted isoindolines coupled with benzimidazoles and benzothiazoles as topoisomerase inhibitors and/or DNA binding compounds with potent antitumor activities.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/química , Benzotiazoles/química , ADN/metabolismo , Isoindoles/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , ADN/química , ADN-Topoisomerasas de Tipo I/química , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoindoles/metabolismo , Isoindoles/farmacología , Células MCF-7 , Microscopía Fluorescente , Relación Estructura-ActividadRESUMEN
A series of lichen secondary metabolites (parietin, atranorin, usnic and gyrophoric acid) and their interactions with calf thymus DNA were investigated using molecular biophysics and biochemical methods. The binding constants K were estimated to range from 4.3×10(5) to 2.4×10(7)M(-1) and the percentage of hypochromism was found to be 16-34% (from spectral titration). The results of spectral measurement indicate that the compounds act as effective DNA-interacting agents. Electrophoretic separation studies prove that from all the metabolites tested in this study, only gyrophoric acid exhibited an inhibitory effect on Topo I (25µM).