Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study

Abstract

DNAase I footprinting has been used to probe the DNA sequence selectivity of the antitumor intercalating agents lucanthone (1), hycanthone (2), 6-chlorolucanthone (7), and four indazole analogs (IA-3-IA-6). The latter have a benzothiopyranoindazole chromophore substituted with a diethylaminoethyl side chain identical to that attached to the thioxanthenone chromophore of compounds 1, 2, and 7. IA-3 and IA-5 are lucanthone analogs bearing a methyl group at position 4, whereas IA-4 and IA-6 are hycanthone analogs bearing a hydroxymethyl group. IA-3 and IA-4 have an additional chloro group at position 6. Studies employing the 160-bp tyrT DNA fragment as substrate to assay inhibition of DNAase I-mediated cleavage show that both lucanthone and hycanthone bind preferentially to AT sites. They discriminate against GC-rich sequences as well as short runs of a single base, which are often cut more readily in the presence of the drugs compared to the control. The indazole analogs exhibit more pronounced selectivity of binding to AT sequences and promote enhanced DNAase I cleavage both at GC-rich sequences and at homooligomeric runs of adenines or thymines. The results of further DNAase I cleavage inhibition assays, performed with three more restriction fragments having different base pair arrangements, are fully consistent with those obtained with the tyrT fragment. They reveal that the preferred binding sequences for lucanthone, hycanthone, and the indazole analogs are predominantly composed of alternating A and T residues.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug—DNA sequence‐dependent interactions analysed by electric linear dichroism

“…The apparent AT selectivity observed under our conditions is not consistent with previous NMR analyses (Feigon et al, 1984) which revealed a marginal G C preference for hycanthone binding to DNA. However, recent investigations by DNAaseI footprinting have fully confirmed the AT selectivity of binding to DNA of hycanthone and its metabolite (Bailly and Waring, 1993b). Needless to say, the observed A T selectivity of the two thioxanthenone derivatives may open the way for future design of AT reading agents based on intercalative binding.…”

Localized Chemical Reactivity in Double‐Stranded DNA Associated with the Intercalative Binding of Benzo[e]Pyridoindole and Benzo[g]Pyridoindole Triple‐Helix‐Stabilizing Ligands

“…Evidently this type of aminoalkylamino side chain, frequently encountered in intercalating drugs (e.g. quinacrine, lucanthone and hycanthone [27]) cannot be responsible for the primary sequence recognition. The lack of any strong sequence selectivity on the part of the two drugs is likely to account (at least partially) for their triple-helix stabilizing property.…”

Small-Molecule Inhibitors of DNA Damage-Repair Pathways: An Approach to Overcome Tumor Resistance to Alkylating Anticancer Drugs

“…Included in this class of APE-1 inhibitors is a series of arylstibinic acids (Figure 9; compounds 13755 and 13743), which although potent at nanomolar concentrations in biochemical experiments, lacked activity in cells [81]. Lucanthone, which inhibits APE-1/REF-1 activity and binds to the protein [82], also interacts with other cellular targets, including DNA via intercalation [83], so the mechanism of action remains uncertain. E3330 (Figure 9), which inhibits APE-1 endonuclease activity at low micromolar concentrations, was originally identified as a specific inhibitor of APE-1 redox activity [84].…”