Design, synthesis, and preliminary biological evaluation of a DNA methyltransferase-directed alkylating agent

ChemBioChem

Volumn 7, Issue 2, 2006, Pages 243-245

  Weller, Rachel L ^a   Rajski, Scott R ^a  

^a UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

Adenosine; Aziridine; Cofactors; DNA damage; Methyltransferase; N mustard

Indexed keywords

ALKYLATING AGENT; DNA METHYLTRANSFERASE;

AMINATION; ARTICLE; DNA ALKYLATION; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; MOLECULAR RECOGNITION; MOLECULAR STABILITY; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; REACTION ANALYSIS; REDUCTION;

ANTINEOPLASTIC AGENTS, ALKYLATING; DNA; DNA MODIFICATION METHYLASES; MOLECULAR STRUCTURE; NITROGEN MUSTARD COMPOUNDS; S-ADENOSYLMETHIONINE;

EID: 32344441148     PISSN: 14394227     EISSN: None     Source Type: Journal    
DOI: 10.1002/cbic.200500362     Document Type: Article

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14. The base ordinarily methylated is shown in bold-face.
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17. Percent yields for lanes 2-5. Reactions for each of the enzymes were as follows: M.Taql: 6, 9, 13, 12%; M.EcoRI: 7, 20, 28, 53%; M.Sssl: 20, 25, 25, 26%; M.Hhal, 15, 38, 41, 42%. For all enzymes, yields of MTase-independent alkylation were < 1%, and the margin of error = ±3% These values were obtained by phosphorimaging of the gels Figure 2 and subsequent data analysis with ImageQuant 2.0 software.
18. All reaction mixtures evaluated in Figure 2 were incubated at 37 C. M.Taql, however, has an optimum temperature of 65 C; it displays markedly lower activity at 37 C. This likely explains the much lower yields of DNA alkylation with 6 by M.Taql relative to other MTases under study.
19. Once attached to one of the two strands, 6 very likely prohibits further enzymatic processing of the complementary strand. Because both strands have an equal probability of being the first to react with 6, a theoretical yield (of radiolabeled and alkylated) of 50% is proposed.
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