XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
41.
NovEL GUaNIDINE DErivaTIvES aND evaLUaTION of THEIr DNA
BINDING affINITIES aND POSSIBLE aNTICaNCEr effECT
Jana Plšíková 1 , Ján Kovaľ 2 , Jaromír Mikeš 2 , Mária Kožurková 1 , Peter Fedoročko 2 ,
Ladislav Janovec 3 , Ján Ungvarský 3 and Danica Sabolová 1
1
Department of Biochemistry UPJŠ Košice,
2
Department of Biology and Ecology UPJŠ Košice,
3
Department of Organic chemistry UPJŠ Košice
Acridine derivatives represent a well known class of multi-faceted anticancer agents that
generally interfere with DNA and inhibit important regulatory enzymes such as topoisomerases.
In order to identify novel anticancer drugs, we evaluated the mechanism
of action of a novel series of 1`,1``-(acridin–3,6–diyl)–3`,3``-dialkyldiguanidines (etyl
to hexyl). The affinity of studied compounds with DNA was investigated by a variety of
techniques including UV-VIS, fluorescence, CD spectroscopy and electrophoresis. Binding
constants for the DNA-drug complexes were determined from spectrofluorimetric titrations,
(K = 1,25 – 5,26 ×10 5 M -1 ). Moreover, these compounds were capable of inhibiting
topoisomerase I. Biological activities of studied derivatives were determined using flow
cytometric methods after 24, 48 and 72 h co-incubation with leukemic cancer cell line
HL-60. The most profound effect on different cell parameters was observed after 72 h
incubation with the pentyl and hexyl derivate. We detected a significant increase in caspase-3
activity, increase of percentage of cells with dissipated mitochondrial membrane
potential, cell accumulation in G1 phase of cell cycle and enhanced DNA fragmentation.
In summary, the studied derivatives are capable of interacting with ctDNA thought
intercalation and inhibiting topoisomerase I. They also display a significant anticancer
effect in HL 60 cells.
Acknowledgement: This work was supported by VEGA 1/0053/08, 1/0097/10 and by the
Slovak Research and Development Agency under contract no. VVCE-0001-07.
XXII. Biochemistry Congress, Martin
159