RESUMEN
The novel benzimidazol-2-yl-fur-5-yl-(1,2,3)-triazolyl dimeric series with aliphatic and aromatic central linkers was successfully prepared with the aim of assessing binding affinity to DNA/RNA and antitrypanosomal activity. UV-Visible spectroscopy, thermal denaturation showed interaction of heterocyclic bis-amidines with ctDNA. Circular dichroism studies indicated uniform orientation of heterocyclic bis-amidines along the chiral double helix axis, revealing minor groove binding as the dominant binding mode. The amidino fragment and 1,4-bis(oxymethylene)phenyl spacer were the main determinants of activity against Trypanosoma brucei. The bis-benzimidazole imidazoline 15c, which had antitrypanosomal potency in the submicromolar range and DNA interacting properties, emerged as a candidate for further structural optimization to obtain more effective agents to combat trypanosome infections.
Asunto(s)
Bencimidazoles/farmacología , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
Novel bis-nucleobase-phenanthridinium conjugates were synthesised and their aqueous solutions spectroscopically characterised. Bis-adenine conjugate revealed in aqueous solutions significantly more pronounced intramolecular aromatic stacking interactions than bis-uracil analogue. In contrast with previously reported poly A recognition by bis-uracil conjugate, recognition of complementary nucleotides and poly U was not observed due to the strong interference of bulk water with hydrogen bonding between nucleobases. The screening of anticancer activity on six human cell lines revealed that tethering of a nucleobase to phenanthridinium moiety diminished antiproliferative potential of phenanthridinium. However, among mono-nucleobase conjugates adenine derivative was found to be the most selective one (MiaPaCa-2, Hep-2).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Nucleótidos/química , Fenantridinas/química , Poli U/química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Células HeLa , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Estructura Molecular , Sensibilidad y Especificidad , Espectrometría de Fluorescencia/métodos , Espectrofotometría Ultravioleta/métodos , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The aim of this review is to summarize the most comprehensive results in the field of bis-aromatic compounds targeting DNA and RNA, whereby both aromatic units of small molecule bind to the polynucleotide by the aromatic stacking interactions. The most recent results about structure - DNA/RNA binding affinity, selectivity and biological implications are discussed for bis-intercalators, sterically restricted macrocyclic and threading bis-aromatics and intercalator - nucleobase conjugates.