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

Autori
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 ; Brozovic, Anamaria ; Horvat, Lucija ; Tumir, Lidija-Marija

Izvornik
Bioorganic chemistry (0045-2068) 127 (2022); 105999, 15

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
DYES ; Benzothiazole ; Piperazine ; DNA and RNA binding ; Fluorescence ; CD spectroscopy ; G-quadruplex binding ; Antiproliferative activity ; Mitochondrial dye ; Theragnostic activity

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Interdisciplinarne prirodne znanosti

POVEZANOST RADA