title: DNA damage and cytotoxicity induced by minor groove binding methyl sulfonate esters.
abstract: Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl sulfonate ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mutant strains defective in base excision repair (tag and/or alkA or apn). The results demonstrate the importance of 3-methyladenine, and in some cases 3-methylguanine, lesions in cellular toxicity, and the dominant protective role of the DNA glycosylases. There is no evidence that the sequence specificity is related to toxicity.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Varadarajan
authors.forename: Dharini
authors.initials: D
authors.lastname: Shah
authors.forename: Prasad
authors.initials: P
authors.lastname: Dande
authors.forename: Samuel
authors.initials: S
authors.lastname: Settles
authors.forename: Fa-xian
authors.initials: FX
authors.lastname: Chen
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
authors.forename: Barry
authors.initials: B
authors.lastname: Gold
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001483:Base Sequence / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004269:DNA, Bacterial / Q000187:drug effects / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D004952:Esters; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D008698:Mesylates / Q000633:toxicity*; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D018736:DNA Adducts; D004269:DNA, Bacterial; D004952:Esters; D008698:Mesylates; C110963:methyl lexitropsin; C045880:methanesulfonic acid; C044502:3-methylguanine; C025946:3-methyladenine; D006147:Guanine; D009429:Netropsin; C008450:7-methylguanine; D000225:Adenine