Novel dications with unfused aromatic systems: trithiophene and trifuran derivatives of furimidazoline.
We report the synthesis, interaction with DNA, topoisomerase II inhibition, and cytotoxicity of two novel unfused aromatic dications derived from the antimicrobial agent furimidazoline. The central diphenylfuran core of furimidazoline has been replaced with a trithiophene (DB358) or a trifuran (DB669) unit and the terminal imidazoline groups were preserved. The strength and mode of binding of the drugs to nucleic acids were investigated by complementary spectroscopic techniques including spectrophotometric, surface plasmon resonance, circular and linear dichroism measurements. The trifuran derivative forms intercalation complexes with double-stranded DNA, whereas the mode of binding of the trithiophene derivative varies depending on the drug/DNA ratio, as independently confirmed by NMR spectroscopic studies performed with (A-T)7 and (G-C)7 oligomers. Two-dimensional NMR data provided a molecular model for the binding of DB358 within the minor groove of the AATT sequence of the decanucleotide d(GCGAATTCGC)(2). DNase I footprinting experiments confirmed the sequence-dependent binding of DB358 to DNA. The trithiophene derivative interacts preferentially with AT-rich sequences at low concentrations, but can accomodate GC sites at higher concentrations. DNA relaxation assays revealed that DB358 stimulated DNA cleavage by topoisomerase II, in contrast to DB669. The substitution of N-alkylamidines for the imidazoline terminal groups abolished the capacity of the drug to poison topoisomerase II. At the cellular level, flow cytometry analysis indicated that DB358, which is about six times more cytotoxic than the trifuran analogue, induced a significant accumulation of HL-60 human leukemia cells in the G2/M phase. The incorporation of thiophene heterocycles appears as a convenient procedure to limit the strict AT selectivity of dications containing an extended unfused aromatic system and to design cytotoxic DNA intercalating agents acting as poisons for human topoisomerase II.
Bilik
P
P
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
Tanious
F
F
Kumar
A
A
Wilson
W D
WD
Boykin
D W
DW
Colson
P
P
Houssier
C
C
Facompré
M
M
Tardy
C
C
Bailly
C
C
D019380:Anti-HIV Agents / Q000737:chemistry*; D002413:Cations, Divalent; D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects*; D018983:DNA Footprinting; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013056:Spectrophotometry, Ultraviolet; D020349:Surface Plasmon Resonance; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D019380:Anti-HIV Agents; D002413:Cations, Divalent; C452825:DB358; C452826:DB669; D004791:Enzyme Inhibitors; D005663:Furans; D007093:Imidazoles; D013876:Thiophenes; D059005:Topoisomerase II Inhibitors; C120946:furimidazoline; D004247:DNA