Targeting DNA with Novel Diphenylcarbazoles
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- 作者：Nathalie Dias ; Ulrich Jacquemard ; Brigitte Baldeyrou ; Christelle Tardy ; Amé ; lie Lansiaux ; Pierre Colson ; Farial Tanious ; W. David Wilson ; Sylvain Routier ; Jean-Yves Mé ; rour ; and Christian
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：December 7, 2004
- 年：2004
- 卷：43
- 期：48
- 页码：15169 - 15178
- 全文大小：515K
- 年卷期：v.43,no.48(December 7, 2004)
- ISSN：1520-4995
文摘
Double-stranded DNA is a therapeutic target for a variety of anticancer and antimicrobialdrugs. Noncovalent interactions of small molecules with DNA usually occur via intercalation of planarcompounds between adjacent base pairs or minor-groove recognition by extended crescent-shaped ligands.However, the dynamic and flexibility of the DNA platform provide a variety of conformations that canbe targeted by structurally diverse compounds. Here, we propose a novel DNA-binding template forconstruction of new therapeutic candidates. Four bisphenylcarbazole derivatives, derived from the combinedmolecular architectures of known antitumor bisphenylbenzimidazoles and anti-infectious dicationiccarbazoles, have been designed, and their interaction with DNA has been studied by a combination ofbiochemical and biophysical methods. The substitutions of the bisphenylcarbazole core with two terminaldimethylaminoalkoxy side chains strongly promote the interaction with DNA, to prevent the heatdenaturation of the double helix. The deletion or the replacement of the dimethylamino-terminal groupswith hydroxyl groups strongly decreased DNA interaction, and the addition of a third cationic side chainon the carbazole nitrogen reinforced the affinity of the compound for DNA. Although the bi- and tridentatemolecules both derive from well-characterized DNA minor-groove binders, the analysis of their bindingmode by means of circular and linear dichroism methods suggests that these compounds form intercalationcomplexes with DNA. Negative-reduced dichroism signals were recorded in the presence of natural DNAand synthetic AT and GC polynucleotides. The intercalation hypothesis was validated by unwindingexperiments using topoisomerase I. Prominent gel shifts were observed with the di- and trisubstitutedbisphenylcarbazoles but not with the uncharged analogues. These observations, together with thedocumented stacking properties of such molecules (components for liquid crystals), prompted us toinvestigate their binding to the human telomeric DNA sequence by means of biosensor surface plasmonresonance. Under conditions favorable to G4 formation, the title compounds showed only a modestinteraction with the telomeric quadruplex sequence, comparable to that measured with a double-strandedoligonucleotide. Their sequence preference was explored by DNase I footprinting experiments from whichwe identified a composite set of binding sequences comprising short AT stretches and a few other mixedAT/GC blocks with no special AT character. The variety of the binding sequences possibly reflects thecoexistence of distinct positioning of the chromophore in the intercalation sites. The bisphenylcarbazoleunit represents an original pharmacophore for DNA recognition. Its branched structure, with two or threearms suitable to introduce a structural diversity, provides an interesting scaffold to built moleculessusceptible to discriminate between the different conformations of nucleic acids.