Syntheses and DNA-binding studies of a series of unsymmetrical cyanine dyes: structural influence on the degree of minor groove binding to natural DNA

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 9; pp. 2369 - 2384
• Main Authors: Karlsson, H.Jonas, Bergqvist, Mattias H., Lincoln, Per, Westman, Gunnar
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-05-2004; Elsevier Science
• Subjects: Binding Sites; Biological and medical sciences; Carbocyanines - chemical synthesis; Carbocyanines - metabolism; Circular Dichroism; DNA - chemistry; DNA - metabolism; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Spectrum Analysis; Sulfur nitrogen heterocycle; Circular dichroism spectrum; Benzoxazole derivatives; Minor groove; Benzothiazole derivatives; In vitro; Cyanine dye; Fluorescence spectrometry; Biological fixation; Structure activity relation; DNA; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.02.006

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Twelve crescent-shaped unsymmetrical dyes have been synthesized and their interactions with DNA have been investigated by spectroscopic methods. A new facile synthetic route to this type of cyanine dyes has been developed, involving the preparation of 6-substituted 2-thiomethyl-benzothiazoles in good yields. The new dyes are analogues to the minor groove binding unsymmetrical cyanine dye, BEBO, recently reported by us. In this dye, the structure of the known intercalating cyanine dye BO was extended with a 6-methylbenzothiazole substituent. Herein we further investigate the role of the extending benzazole heterocycle, as well as of the pyridine or quinoline moiety of the cyanine chromophore, for the binding mode of these crescent-shaped dyes to calf thymus DNA. Flow LD and CD studies of the 12 dyes show that the extent of minor groove binding to mixed sequence DNA varies significantly between the dyes. We find that hydrophobicity and size are the crucial parameters for recognition of the minor groove.
The relatively high fluorescence quantum yield of many of these cyanines bound to DNA, combined with their absorption at long wavelengths, may render them useful in biological applications. In particular, two of the benzoxazole containing dyes BOXTO and 2-BOXTO show a high degree of minor groove binding and quantum yields of 0.52 and 0.32, respectively, when bound to DNA.