3,6-bis(3-alkylguanidino)acridines as DNA-intercalating antitumor agents.
A series of 3,6-bis(3-alkylguanidino) acridines was prepared and the interaction of these novel compounds with calf thymus DNA was investigated with UV-vis, fluorescence and circular dichroism spectroscopy, in addition to DNA melting techniques. The binding constants K were estimated to range from 1.25 to 5.26 × 10(5) M(-1), and the percentage of hypochromism was found to be 17-42% (from spectral titration). UV-vis, fluorescence and circular dichroism measurements indicated that the compounds act as effective DNA-intercalating agents. Electrophoretic separation proved that ligands 6a-e relaxed topoisomerase I at a concentration of 60 μM, although only those with longer alkyl chains were able to penetrate cell membranes and suppress cell proliferation effectively. The biological activity of novel compounds was assessed using different techniques (cell cycle distribution, phosphatidylserine externalization, caspase-3 activation, changes in mitochondrial membrane potential) and demonstrated mostly transient cytostatic action of the ethyl 6c and pentyl 6d derivatives. The hexyl derivative 6e proved to be the most cytotoxic. Different patterns of cell penetration were also observed for individual derivatives. Principles of molecular dynamics were applied to explore DNA-ligand interactions at the molecular level.
Department of Biochemistry, P. J. Safarik University in Kosice, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
Jana
J
Plsikova
Ladislav
L
Janovec
Jan
J
Koval
Jan
J
Ungvarsky
Jaromir
J
Mikes
Rastislav
R
Jendzelovsky
Peter
P
Fedorocko
Jan
J
Imrich
Pavol
P
Kristian
Jana
J
Kasparkova
Viktor
V
Brabec
Maria
M
Kozurkova
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D009691:Nucleic Acid Denaturation; D010718:Phosphatidylserines / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D006146:Guanidines; D007364:Intercalating Agents; D010718:Phosphatidylserines; D004247:DNA; C427203:calf thymus DNA; D053148:Caspase 3; D004264:DNA Topoisomerases, Type I