title: Modification of cellular DNA by synthetic aziridinomitosenes.
abstract: Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA-protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA-DNA and DNA-protein adduct formation as mechanisms for inducing cytotoxic effects.
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: chrismmallory@gmail.com.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Mallory
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: ryancarfi@u.boisestate.edu.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Carfi
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: philmoon@u.boisestate.edu.
authors.forename: SangPhil
authors.initials: S
authors.lastname: Moon
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: kencornell@boisestate.edu.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Cornell
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: dwarner@boisestate.edu.
authors.forename: Don L
authors.initials: DL
authors.lastname: Warner
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D008937:Mitomycins / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D008937:Mitomycins; D004247:DNA
keywords: Alkylating agents; Aziridinomitosene; DNA adducts; Mitomycin C