Chemical Properties of the Leinamycin-Guanine Adduct in DNA
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- 作者：Tony Nooner ; Sanjay Dutta ; and Kent S. Gates
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：July 2004
- 年：2004
- 卷：17
- 期：7
- 页码：942 - 949
- 全文大小：125K
- 年卷期：v.17,no.7(July 2004)
- ISSN：1520-5010
文摘
The reaction of the antitumor agent leinamycin with thiols converts this natural productinto an episulfonium ion that alkylates the N7-position of guanine residues in double-strandedDNA. It is reported here that depurination of this adduct is unusually facile, occurring witha half-life of about 3.5 h at pH 7 and 37 
C in duplex DNA. This is one of the most rapiddepurination reactions ever observed for an N7-alkylguanine residue. The rate constant forthe depurination reaction was measured at several temperatures, and the activation parameterswere calculated from the data. The energy of activation (Ea) for this reaction is 24.6 kcal/mol,and the Arrhenius A value is 1.2 × 1013 s-1. These values correspond to a 
H
= 24.0 kcal/moland S = -0.78 eu and are consistent with the expected unimolecular (DN + AN) mechanismfor the depurination reaction. Changes in ionic strength (0-500 mM NaCl) or pH (3-8) do notsignificantly alter the rate of depurination, and the base excision repair protein Aag, whichremoves a variety of N7-alkylguanine residues from duplex DNA, does not excise theleinamycin-guanine adduct. Possible biological implications of this rapid depurination processare considered. Finally, during the course of these studies, the release of hydrolyzed leinamycin(4; Scheme 1) from leinamycin-modified DNA was observed. This result suggests thatleinamycin may be a reversible DNA alkylating agent.
C in duplex DNA. This is one of the most rapiddepurination reactions ever observed for an N7-alkylguanine residue. The rate constant forthe depurination reaction was measured at several temperatures, and the activation parameterswere calculated from the data. The energy of activation (Ea) for this reaction is 24.6 kcal/mol,and the Arrhenius A value is 1.2 × 1013 s-1. These values correspond to a H = 24.0 kcal/moland S = -0.78 eu and are consistent with the expected unimolecular (DN + AN) mechanismfor the depurination reaction. Changes in ionic strength (0-500 mM NaCl) or pH (3-8) do notsignificantly alter the rate of depurination, and the base excision repair protein Aag, whichremoves a variety of N7-alkylguanine residues from duplex DNA, does not excise theleinamycin-guanine adduct. Possible biological implications of this rapid depurination processare considered. Finally, during the course of these studies, the release of hydrolyzed leinamycin(4; Scheme 1) from leinamycin-modified DNA was observed. This result suggests thatleinamycin may be a reversible DNA alkylating agent.