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Styryl dyes with N-Methylpiperazine and N-Phenylpiperazine Functionality: AT-DNA and G-quadruplex binding ligands and theranostic agents

Zonjić, Iva; Radić Stojković, Marijana; Crnolatac, Ivo; Tomašić Paić, Ana; Pšeničnik, Silvia; Vasilev, Aleksey; Kandinska, Meglena; Mondeshki, Mihail; Baluschev, Stanislav; Landfester, Katharina; Glavaš-Obrovac, Ljubica; Jukić, Marijana; Kralj, Juran; Brozović, Anamaria; Horvat, Lucija; Tumir, Lidija-Marija (2022) Styryl dyes with N-Methylpiperazine and N-Phenylpiperazine Functionality: AT-DNA and G-quadruplex binding ligands and theranostic agents. Bioorganic Chemistry, 127 . pp. 1-15. ISSN 0045-2068

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New monomethine, unsymmetrical styryl dyes consisting of benzothiazole and N-methylpiperazine or N-phenylpiperazine scaffolds were synthesized, and their binding affinities for different ds-polynucleotides and G-quadruplex were studied. Substitution of piperazine unit with methyl or phenyl group strongly influenced their binding modes, binding affinities, spectroscopic responses and antiproliferative activities. Compounds with N-methylpiperazine substituents showed a significant preference for AT-DNA polynucleotides and demonstrated AT-minor groove binding, which manifested in strong fluorescence increase, significant double helix stabilization, and positive induced circular dichroism spectra. These compounds formed complexes with G-quadruplex by π-π stacking interactions of dye with the top or bottom G-tetrad. Bulkier compounds with N-phenylpiperazine function are probably bound to ds-polynucleotide by partial intercalation between base pairs. On the other hand, they showed stronger stabilization of G-quadruplex compared to methyl-substituted compounds. Fluorimetric titrations pointed to possible mixed stoichiometry’s: 1:1 complex with π-π stacking interactions of dye on the top or bottom G- tetrad and 1:2 complex with dye positioned between two G-quadruplex molecules. Bulkier dyes with N-phenylpiperazine fragments demonstrated micromolar and submicromolar antiproliferative activity that was especially pronounced for leukaemia and lymphoma. Flow cytometric assay shows dose- and time-dependent increase in SubG0/G1 phase. Furthermore, the compounds enter the cells readily and accumulate in the mitochondrial space, co-localize with the standard mitochondrial markers.

Item Type: Article
Uncontrolled Keywords: DYES ; Benzothiazole ; Piperazine ; DNA and RNA binding ; Fluorescence ; CD spectroscopy ; G-quadruplex binding ; Antiproliferative activity ; Mitochondrial dye ; Theragnostic activity
Subjects: NATURAL SCIENCES > Chemistry > Physical Chemistry
NATURAL SCIENCES > Chemistry > Analytic Chemistry
NATURAL SCIENCES > Chemistry > Organic Chemistry
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions: Division of Molecular Biology
Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Molekularno prepoznavanje DNA:RNA hibridnih i višelančanih struktura u bioanalitičkim i in vitro sustavima-DNARNAHyB-MolBioMarijana Radić StojkovićIP-2018-01-4694HRZZ
Depositing User: Lidija-Marija Tumir
Date Deposited: 07 Feb 2024 14:43
DOI: 10.1016/j.bioorg.2022.105999

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