Control of the DNA‐Binding and Antiproliferative Properties of Hydroxybenzo[b]quinolizinium Derivatives with pH and Light. Issue 2 (30th November 2016)

• Record Type: Journal Article
• Authors: Schäfer, Katy; Ihmels, Heiko; Porcù, Elena; Viola, Giampietro
• Is Part Of: Chemistry. Volume 23:Issue 2(2017)
• Page Start: 370
• Page End: 379
• Publication Date: 2016-11-30
• Subjects: antiproliferation -- DNA damage -- ligand design -- nitrogen heterocycles -- photochemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201603807
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The interactions of 8‐hydroxybenzo[ b ]quinolizinium and 9‐hydroxybenzo[ b ]quinolizinium with DNA are investigated in detail. Specifically, spectrophotometric and spectrofluorimetric titrations, thermal DNA‐denaturation experiments as well as CD‐ and LD‐spectroscopic analysis show that a pH shift by just one or two orders of magnitude has a significant impact on the interactions of the acidic ligands with the nucleic acid. Both ligands bind with high affinity to DNA at pH 6 ( Kb ≈10 5 m −1 ). At pH 7 or 8, however, the binding interactions are much weaker because of the formation of the corresponding charge‐neutral conjugate bases, the affinity to DNA of which is reduced because of the resulting lack of a positive charge. Notably, the variation of DNA affinity occurs in a range that corresponds to the fluctuations of pH values under physiological conditions, so that these ligands may be employed to target DNA in tissue with particular pH values, especially, cancer cells. The antiproliferative activity of the title compounds under different conditions is also investigated. In the absence of irradiation, both compounds show only a modest cytotoxicity toward cancer cells. However, upon irradiation, even at low UV‐A doses, a significant reduction of cell viability of tumor cell lines is induced by the ligands. Abstract : pH and light make the difference : Switching the pH from slightly alkaline to slightly acidic results in an increased affinity of hydroxybenzo[ b ]quinolizinium intercalators towards DNA (see scheme). In addition, the moderate cytotoxicity of these ligands rises significantly upon irradiation with UV‐A light.