Molecular Recognition between a New Pentacyclic Acridinium Salt and DNA Sequences Investigated by Optical Spectroscopic Techniques, Proton Nuclear Magnetic Resonance Spectroscopy, and Molecular Modeli
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- 作者：Clare E. Bostock-Smith ; Elena Gimé ; nez-Arnau ; Sotiris Missailidis ; Charles A. Laughton ; Malcolm F. G. Stevens ; and Mark S. Searle
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：May 25, 1999
- 年：1999
- 卷：38
- 期：21
- 页码：6723 - 6731
- 全文大小：178K
- 年卷期：v.38,no.21(May 25, 1999)
- ISSN：1520-4995
文摘
A pentacyclic acridine, 1H-2,3-dihydroindolizino[7,6,5-kl]acridinium chloride (1), related instructure to tetra- and pentacyclic marine natural products, has previously been shown to induce apoptosisin breast and non-small-cell lung tumor cell lines and shows significant differences in biological potencyand antitumor profile from other intercalating agents based on the acridine framework. We report on themolecular recognition of the acridinium salt with DNA, quantified by optical spectroscopic methods, andhave compared these results with the clinical agent amsacrine (m-AMSA). The results point to anintercalative association between 1 and G-C-rich sequences of DNA. We have synthesized a hexamerduplex d(ACGCGT)2, presenting two potential 5'-CpG recipient sites, and have investigated in detail byNMR and molecular modeling methods the orientational preferences of 1, particularly with regard to thepyrrolidine ring system. On the basis of the intermolecular nuclear Overhauser effect (NOE) data, fourpossible intercalation models were considered; no single model produced a significantly better fit thanany of the others. The best fit to the experimental data was obtained by considering a dynamic equilibriumbetween the different intercalated orientations with the drug maximizing 
-overlap with the G-C basepairs at the intercalation site. We found little evidence for any degree of groove specificity imparted bythe pyrrolidine ring. If these simulations have biological relevance they suggest that, at most, the agentinduces only a transitory hot spot in the DNA which, evidently, is sufficient to be sensed by damage-recognition mechanisms of the cell.
-overlap with the G-C basepairs at the intercalation site. We found little evidence for any degree of groove specificity imparted bythe pyrrolidine ring. If these simulations have biological relevance they suggest that, at most, the agentinduces only a transitory hot spot in the DNA which, evidently, is sufficient to be sensed by damage-recognition mechanisms of the cell.