Molecular recognition between a new pentacyclic acridinium salt and DNA sequences investigated by optical spectroscopic techniques, proton nuclear magnetic resonance spectroscopy, and molecular modeling.
A pentacyclic acridine, 1H-2,3-dihydroindolizino[7,6,5-kl]acridinium chloride (1), related in structure to tetra- and pentacyclic marine natural products, has previously been shown to induce apoptosis in breast and non-small-cell lung tumor cell lines and shows significant differences in biological potency and antitumor profile from other intercalating agents based on the acridine framework. We report on the molecular recognition of the acridinium salt with DNA, quantified by optical spectroscopic methods, and have compared these results with the clinical agent amsacrine (m-AMSA). The results point to an intercalative association between 1 and G-C-rich sequences of DNA. We have synthesized a hexamer duplex d(ACGCGT)2, presenting two potential 5'-CpG recipient sites, and have investigated in detail by NMR and molecular modeling methods the orientational preferences of 1, particularly with regard to the pyrrolidine ring system. On the basis of the intermolecular nuclear Overhauser effect (NOE) data, four possible intercalation models were considered; no single model produced a significantly better fit than any of the others. The best fit to the experimental data was obtained by considering a dynamic equilibrium between the different intercalated orientations with the drug maximizing pi-overlap with the G-C base pairs at the intercalation site. We found little evidence for any degree of groove specificity imparted by the pyrrolidine ring. If these simulations have biological relevance they suggest that, at most, the agent induces only a transitory hot spot in the DNA which, evidently, is sufficient to be sensed by damage-recognition mechanisms of the cell.
Bostock-Smith
C E
CE
Department of Chemistry, Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, United Kingdom.
Giménez-Arnau
E
E
Missailidis
S
S
Laughton
C A
CA
Stevens
M F
MF
Searle
M S
MS
D000166:Acridines / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004996:Ethidium / Q000737:chemistry; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D013056:Spectrophotometry, Ultraviolet
C119396:2,3-dihydroindolizino(7,6,5-kl)acridinium chloride; D000166:Acridines; D007211:Indoles; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D004247:DNA; D004996:Ethidium