DNA damage agents

Begley TJ, Samson FD. Network responses to DNA damaging agents. DNA Repair (Amst) 2004 3 1123-32. 

A few interesting organic molecules may possess the ability to release hydroxyl radical under physiological conditions. The most extensively studied of these is 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine, 95, Scheme 8.32). Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. The biological activity of... 

Denison SH, Kafer E, May GS 1993 Mutation in the bimD gene of Aspergillus nidulans confers a conditional mitotic block and sensitivity to DNA damaging agents. Genetics 134 1085—1096... 

ABT-888 (22) shows limited activity as monotherapy however, it strongly potentiates the activity of multiple DNA-damaging agents in preclinical models [39]. ABT-888 potentiated TMZ in a glioma model in a dose-dependent manner, with maximal efficacy achieved at 50 mg/ kg, which reduced tumor volume by 63%, 44% better than TMZ alone. In the MX-1 breast xenograft model, ABT-888, at 5 mg/ kg/ day in combination with cisplatin, caused sustained regressions in 8/9 mice compared to 3/9 for cisplatin monotherapy. 

I would like to describe our investigations, performed in collaboration with Jeffrey Miller. To begin, I will briefly outline the genetic system developed by Miller which permits a rapid, rigorous determination of the position and kinds of mutants induced in a particular gene by DNA damaging agents. 

Luminescent bacteria also allow detection of the carcinogenic effect of ge-notoxics. A dark mutant of a Photobacterium or Vibrio strain that can revert back to luminescence at an increased rate in the presence of base-substitutes or frame-shifts agents, DNA-damaging agents, DNA synthesis inhibitors, and DNA intercalating agents can be employed [171, 172],... 

Many quinones (including anthracyclines considered above) are well-known prooxidants that makes them potential DNA damaging agents. It has been shown that menadione (2-methyl-1,4-naphthoquinone), a redox cycling quinone, induced single- and double-strand... 

These not only exhibit all the structural and spectroscopic characteristics of anomeric amides 2, their reactivity patterns embrace a range of reactions at the amide nitrogen that in many respects parallel those at a saturated carbon.37 46 In addition, they are mutagenic as well as DNA damaging agents that have anticancer capability.37,38,40,46 50 To date nearly a hundred of these have been synthesised in our laboratory while, recently, a range of urea and urethane analogues have also been reported.51 53... 

From appraisal of their respective resonance stabilisation, arylnitrenium ions and alkoxynitrenium ions should form with similar facility. On account of the fact that A-acetoxy-A-acetyl arylamines 7 are penultimate carcinogens in the metabolism of aromatic amines, A-acyloxy-A-alkoxyamides 3 were designed to test their potential as DNA-damaging agents. 

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