PubMed · 4818916
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J A Edgar. 1974-03-08. Ascorbic acid and biological alkylating agents.. https://doi.org/10.1038/248136a0
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Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the rate constants for nucleophile trapping and of the pKa values for the protonated aziridinyl quinones. A linear free energy relationship, including the antitumor agent DZQ, as well as other synthetic quinone derivatives, was obtained as a result of this study. Protonated DZQ has the relatively high pKa value of 3.8, which explains the enhanced cross-linking of DNA by DZQ and other related aziridinyl quinones at pH 4. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen, but the dependence of pKa values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Also investigated were the DNA alkylation reactions of protonated aziridinyl quinones. At the outset of this study, we postulated that these "hard" electrophiles would alkylate the phosphate backbone of DNA. Bulk DNA is up to 35% alkylated by protonated aziridinyl quinones as judged by the incorporation of the quinone chromophore into the DNA. The presence of phosphate alkylation was verified by a 1H-31P NMR correlation experiment with DZQ-alkylated hexamer. Our modeling studies present a new picture of DZQ alkylation of DNA, where there is competition between N(7) and phosphate alkylation. The conclusions of this part of our study are that the phosphate backbone should be considered as a possible target of any DNA-alkylating agent and that an assessment of phosphate alkylation is best made with a 1H-31P NMR correlation experiment. Finally, the benzimidazole-based aziridinyl quinone 2 was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring. This reaction was used to tag the phosphate backbone of DNA with aminoethyl groups. Such tags render anionic phosphates cationic and could also be employed as points of attachment for chromophores, spin labels, or other moieties to DNA.
Inferential test strategies for multi-arm trials are adapted or proposed for the special situation when more than one dose of a test treatment, placebo and active control(s) are compared. This includes between doses, dose-placebo and dose-active-control comparisons. The procedures refer to situations when detailed comparisons make sense only if the sensitivity of the trial has been shown, for example, if a dose-response relationship or a difference between active control and placebo has been established. Split strategies, hierarchical (assuming an order restriction among doses) or linked procedures are introduced. In linked procedures, equivalence to the active control will be established only if the dose is also shown to be effective as compared to placebo. All the inferential procedures control the experimentwise error rate in the strong sense for the respective sets of null hypotheses considered.
Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also to tumor formation, as revealed by the response of MGMT transgenic and knockout mice. Overexpression of genes involved in base excision repair (N-methylpurine-DNA glycosylase, apurinic endonuclease, DNA polymerase beta) is in most cases not beneficial in increasing the protection level, whereas their down-modulation or inactivation increases cellular sensitivity. This indicates that non-repaired base N-alkylation lesions and/or repair intermediates possess genotoxic potential. Modulation of mismatch repair and poly(ADP)ribosyl transferase has also been shown to affect the cellular response to alkylating agents. Furthermore, the role of Fos, Jun and p53 in cellular defense against alkylating mutagens is discussed.