2. Academic Validation
  3. Modification of cellular DNA by synthetic aziridinomitosenes

Modification of cellular DNA by synthetic aziridinomitosenes

  • Bioorg Med Chem. 2015 Dec 1;23(23):7378-85. doi: 10.1016/j.bmc.2015.10.028.
Chris M Mallory 1,  Ryan P Carfi 2,  SangPhil Moon 3,  Kenneth A Cornell 4,  Don L Warner 5
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: chrismmallory@gmail.com.
  • 2 Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: ryancarfi@u.boisestate.edu.
  • 3 Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: philmoon@u.boisestate.edu.
  • 4 Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: kencornell@boisestate.edu.
  • 5 Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA. Electronic address: dwarner@boisestate.edu.
PMID: 26541587 DOI: 10.1016/j.bmc.2015.10.028
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.

Keywords

Alkylating agents; Aziridinomitosene; DNA adducts; Mitomycin C.

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