DNA structural similarity in the 2:1 complexes of the antitumor drugs trabectedin (Yondelis) and chromomycin A3 with an oligonucleotide sequence containing two adjacent TGG binding sites on opposing strands.
Yondelis (trabectedin) is an antitumor ecteinascidin that binds covalently to the 2-amino group of the central guanine in the minor groove of selected DNA pyrimidine-G-G and purine-G-C triplets. Chromomycin A3 is an aureolic acid derivative that binds noncovalently to the DNA minor groove in G/C-rich triplet sites as a metal-chelated dimer. Despite their different binding modes, the cytotoxicity profiles of these two drugs, as assessed in the COMPARE analysis carried out by the National Cancer Institute on data from 60 human tumor cell lines, are highly correlated (Pearson's correlation coefficient of 0.96). We now report that in an oligonucleotide containing the "natural bending element" TGGCCA, the structural distortions inflicted by the tail-to-tail bonding of two trabectedin molecules to adjacent target sites on opposing strands are strikingly similar to those observed in a crystal containing d(TTGGCCAA)2 and two bound chromomycin A3 molecules arranged in a head-to-tail orientation in the minor groove. In both complexes, the double helix is characterized by being considerably unwound and possessing a notably widened minor groove. Binding of the drugs to this sequence could be favored by the distinct bends at each of the TpG steps that are already present in the free oligonucleotide. Simultaneous drug binding to the two strands in the manner described here is proposed to stabilize the helical structure of duplex DNA to prevent or hamper strand separation and stall replication and transcription forks.
Marco
Esther
E
Departamento de Farmacología, Universidad de Alcalá, E-28871 Alcalá de Henares, Madrid, Spain.
Gago
Federico
F
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D014128:Chromomycin A3 / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D009841:Oligonucleotides; D044005:Tetrahydroisoquinolines; D004247:DNA; D014128:Chromomycin A3; D000077606:Trabectedin