Intercalation of imidazoacridinones to DNA and its relevance to cytotoxic and antitumor activity.
Imidazoacridinones (IA) are a class of antitumor agents which includes C-1311, an interesting drug in clinical trials. This study investigated the mechanism of IA binding to DNA for a series of 13 analogs that differ in their cytotoxic potency. Using C-1311 as a model compound, crystallographic, spectroscopic and biochemical techniques were employed to characterize drug-DNA interactions. X-ray crystallographic analysis revealed a planar structure of imidazoacridinone core that is capable of intercalative DNA binding. Accordingly, C-1311 binding to DNA followed 'classical' pattern observed for intercalation, as proved by the DNA topoisomerase I-unwinding experiments, with relatively weak binding affinity (K(i)=1.2 x 10(5)M(-1)), and the binding site size of 2.4 bp. Other IA also bound to DNA with the binding affinity in the range of 10(5)M(-1) and binding site size of 2-3 bp, suggesting a prevalence of the intercalative mechanism, similar to C-1311. Considerable DNA binding affinity was displayed by all the highly cytotoxic derivatives. However, none of the analyzed drug-DNA binding parameters was significantly correlated with IA biological activities such as cell growth, DNA and RNA synthesis inhibition, or tumor growth inhibition, which suggests that the IA ability to non-covalently bind to DNA is not crucial for their biological activity. These results show that the ability to intercalate into DNA is a prominent attribute of IA, although factors other than intercalative binding seem to be required for the biological activities of IA drugs.
Dziegielewski
Jaroslaw
J
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdańsk, Narutowicza 11/12, 80-952, Gdańsk, Poland.
Slusarski
Bartlomiej
B
Konitz
Antoni
A
Skladanowski
Andrzej
A
Konopa
Jerzy
J
D000609:Aminoacridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D007939:Leukemia L1210; D051379:Mice; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013054:Spectrophotometry, Atomic; D013056:Spectrophotometry, Ultraviolet
D000609:Aminoacridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D012313:RNA; C098965:C 1311