Synthesis, cytotoxic activities and proposed mode of binding of a series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines.
A series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines have been prepared and their antiproliferative properties have been tested against HT-29 cell lines. Compounds 6b and 6d showed an interesting cytotoxic profile and were subjected to further cytotoxic evaluation, DNA binding properties and molecular modelling studies. The evaluation of the cytotoxic activity of compounds 6b and 6d against pairs of cisplatin-sensitive and -resistant ovarian tumour cells shows that both compounds may be endowed with interesting antitumour properties because they are able to circumvent cisplatin resistance in A2780cisR, CH1cisR and Pam 212-ras tumour cells. On the other hand, DNA binding data indicate that compounds 6b and 6d are able to intercalate stronger than acridine within the double helix. Both compounds displace ethidium bromide with an efficiency ten times higher than acridine from several linear double-stranded DNAs and induce 43 degrees unwinding in supercoiled pBR322 DNA while acridine unwinds pBR322 DNA by only 24 degrees. Altogether these data indicate that the significant conformational changes induced by compounds 6b and 6d in the double helix are due to a bis-intercalative DNA binding mode. We propose that binding to DNA through bisintercalation might be at least in part responsible for the remarkable cytotoxic properties of these acridine derivatives. The complex of 6b with d(GCGCGC)(2) in the four possible orientations that the ligand can adopt when binding to the DNA hexamer have been modelled and subjected to molecular dynamics simulations with the aim of evaluating the binding preferences of this bisintercalating agent into the DNA molecule. The predictions suggest that 6b binds to d(GCGCGC)(2) with a parallel orientation of the chromophores relative to each other and with a preference for binding through the minor groove of the hexamer. The possible relevance of these findings to the process of bisintercalation and the antitumour profile of these compounds is discussed in this paper.
Braña
Miguel F
MF
Departamento de Química Orgánica y Farmacéutica, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Boadilla del Monte, E-28668 Madrid, Spain. mfbrana@ceu.es
Casarrubios
Luis
L
Domínguez
Gema
G
Fernández
Carlos
C
Pérez
José M
JM
Quiroga
Adoración G
AG
Navarro-Ranninger
Carmen
C
de Pascual-Teresa
Beatriz
B
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002945:Cisplatin / Q000494:pharmacology; D004278:DNA, Superhelical / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000166:Acridines; D000588:Amines; D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D007364:Intercalating Agents; D008024:Ligands; C464528:N,N'-bis(2-((1-amino-9-oxo-9,10-dihydroacridine-4-carbonyl)amino)ethyl)-N,N'-dimethylpropylenediamine; D009841:Oligonucleotides; D002945:Cisplatin