Effects of Compound Structure on Carbazole Dication-DNA Complexes: Tests of the Minor-Groove Complex Models

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• 作者：Farial A. Tanious ; Daoyuan Ding ; Donald A. Patrick ; Christian Bailly ; Richard R. Tidwell ; and W. David Wilson
• 刊名：Biochemistry
• 出版年：2000
• 出版时间：October 3, 2000
• 年：2000
• 卷：39
• 期：39
• 页码：12091 - 12101
• 全文大小：361K
• 年卷期：v.39,no.39(October 3, 2000)
• ISSN：1520-4995

文摘

Carbazole dications have shown excellent activity against opportunistic infections, but theyare quite different in structure from previously studied unfused aromatic cations that function by targetingthe DNA minor groove. In a previous report [Tanious, F. A., Ding, D., Patrick, D. A., Tidwell, R. R., andWilson, W. D. (1997) Biochemistry 36, 15315-15325] we showed that, despite their fused ring structure,the carbazoles also bind in A/T sequences of the DNA minor groove and we proposed models for thecarbazole-DNA complexes with the carbazole nitrogen facing out of the groove for 3,6 substitutedcompounds but into the groove in 2,7 carbazoles. To test and refine the models, carbazole-N-methylsubstituted derivatives have been synthesized in both the 3,6 and 2,7 series as well as a new 2,6 substitutedNH derivative that is intermediate in structure. Footprinting results indicate a broad AT specificity ofcarbazole binding and a pattern in agreement with a minor groove complex. Surface plasmon resonancebiosensor analysis of carbazole binding to an oligomer with an AATT central sequence indicated that the2,7 NH compound has the largest binding constant. Both the 3,6 NH and NMe compounds bind withsimilar equilibrium constants that are less than for the 2,7 NH compound. The 2,7 NMe compound hasthe lowest binding constant of all the carbazoles. Spectroscopic results are also similar for the two 3,6derivatives but are quite different for the 2,7 NH and NMe carbazole dications. Structural analysis ofcarbazole complexes with an AATT sequence by 2D NMR methods also supported a minor groove complexof the carbazoles in orientations in agreement with the previously proposed models. From these results,it is clear that the fused ring carbazoles can bind strongly in the DNA minor groove with a broad A/Tspecificity and that the 2,7 and 3,6 substituted carbazoles bind to the minor groove in opposite orientations.