RESUMEN
The synthesis and evaluation of the novel head-to-head bisbenzimidazole compound 2,2-bis[4'-(3' '-dimethylamino-1' '-propyloxy)phenyl]-5,5-bi-1H-benzimidazole is described. An X-ray crystallographic study of a complex with the DNA dodecanucleotide sequence d(CGCGAATTCGCG) shows the compound bound in the A/T minor groove region of a B-DNA duplex and that the head-to-head bisbenzimidazole motif hydrogen-bonds to the edges of all four consecutive A:T base pairs. The compound showed potent growth inhibition with a mean IC(50) across an ovarian carcinoma cell line panel of 0.31 microM, with no significant cross-resistance in two acquired cisplatin-resistant cell lines and a low level of cross-resistance in the P-glycoprotein overexpressing acquired doxorubicin-resistant cell line. Studies with the hollow fiber assay and in vivo tumor xenografts showed some evidence of antitumor activity.
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , ADN/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Cisplatino/farmacología , Cristalografía por Rayos X , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Desnudos , Modelos Moleculares , Relación Estructura-Actividad , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
The bis-dimethylaminoethyl derivative of quindoline (10H-indolo[3,2-b]quinoline), an alkaloid from the West African shrub Cryptolepis sanguinolenta, has been synthesised. This has been shown to have modest cytotoxicity, as well as inhibitory activity against the telomerase enzyme. It is hypothesised that the latter activity is due to stabilisation of an intermediate guanine-quadruplex complex, in accordance with computer modelling.