9-[(10-(aden-9-yl)-4,8-diazadecyl)amino]-6-chloro-2-methoxy-acridine incises DNA at apurinic sites

Abstract

The incision of DNA at apurinic/apyrimidinic sites (AP-sites) by chloro-6-methoxy-2 [(adenyl-9)-11)-4,8 diazadecyl]amino-9 acridine (Ade-Z-Acr), a 9-aminoacridine linked to an adenine, at nanomolar concentrations is described. Moreover, this drug, Ade-Z-Acr, is one of the most efficient drugs which cleaves DNA at AP-sites. The high activity is the result of the composition of the drug, since the individual components have no incising activity in the concentration range studied. The termini left by the Ade-Z-Acr molecule are a 3'deoxyribose and a 5'nucleotide. The termini and the inability of the Ade-Z-Acr to incise DNA with reduced AP-sites suggest that the mechanism of cleavage is beta-elimination.

Physical association of the 2,6-diamino-4-hydroxy-5N-formamidopyrimidine-DNA glycosylase of Escherichia coli and an activity nicking DNA at apurinic/apyrimidinic sites.

“…In addition, it does not cleave DNA containing reduced AP sites. These data suggest that the nicking of the DNA at AP sites occurs by a mechanism of, elimination as observed previously for other enzymes (36,37) and APnicking agents (22,26). Therefore, the AP-nicking activity of the Fapy-DNA glycosylase should be referred to as an AP lyase (36).…”

“…The reaction was stopped by extracting the nicking agents from the reaction solution using phenol, followed by chloroform/isoamyl alcohol, and the DNA was ethanol precipitated. The relative amounts of nicked and supercoiled DNA were quantitated using densitometry following agarose gel electrophoresis (22,23). For the nicking of pBR322 DNA containing AP sites, the following conditions were used: bacteriophage T4 UV endonuclease (10 AP-nicking units), Fapy-DNA glycosylase (20 AP-nicking units), endonuclease III (5 AP-nicking units), endonuclease IV (3 AP-nicking units), Ade-Z-Acr (22) (13).…”

“…For the nicking of pBR322 DNA containing AP sites, the following conditions were used: bacteriophage T4 UV endonuclease (10 AP-nicking units), Fapy-DNA glycosylase (20 AP-nicking units), endonuclease III (5 AP-nicking units), endonuclease IV (3 AP-nicking units), Ade-Z-Acr (22) (13). Nick-translation of pBR322 DNA incised at AP sites was performed by using E. coli DNA polymerase I (22,29 Table 1 show that these two activities copurify. Furthermore, the ratio of Fapy-DNA glycosylase activity/AP-nicking activity is essentially constant over the Fapy-DNA glycosylase peaks for all of the columns and is shown for the Mono S column in Fig.…”

Abasic DNA structure, reactivity, and recognition

“…118,119 In an effort to precise the mode of interaction and cleavage, and to devise more efficient molecules, a series of drugs were prepared in which the three modular constituents were successively varied ( Figure 10). The strong amino-acridine intercalator was replaced by the poor DNA-binder aminoquinoline, adenine was substituted by 2,6-diaminopurine that presents larger H-bonding capacities or by a tricyclic analogue, 120 and the linking chain was varied in length and nature, including polymethylenes, amino and amido functions.…”

Antibiotic Drugs Aminoglycosides Cleave DNA at Abasic Sites: Shedding New Light on Their Toxicity?

“…Conjugates composed of three parts, an acridine intercalator linked by a diamino chain to a nucleobase diaminopurine (DTAc) or adenine (ATAc) (Figure 2), have also been shown to exhibit cleavage efficiency at apurinic sites in plasmidic DNA at nanomolar concentrations. 72,73 Since abasic sites are formed in the cell with fairly high frequency either spontaneously or enzymatically as intermediates during the repair process of modified bases (base excision repair pathway (BER)), 59 compounds that cleave at abasic sites are thus good candidates for designing drugs able to interfere with the repair process. For instance, an inhibitory effect might be useful to sensitize tumor cells to alkylating drugs.…”