Synthesis of C6/C7 Dimethyl Aziridinomitosene Analog for the Analysis of DNA-Protein Crosslink Formation
Abstract
Aziridinomitosenes are synthetic derivatives of the antitumoral/antibiotic drug mitomycin C, a compound that has been implemented in chemotherapy regimens to treat a variety of cancers over the last few decades. Mitomycin C and Aziridinomitosenes both have a distinct quinone-based chemical structure that facilitates their formation of sequence-specific, cytotoxic DNA interstrand cross-links. Quinone-based drugs, including mitomycin C, have traditionally required a hypoxic environment and reductive activation to form DNA lesions. But recent studies have shown that an unsubstituted aziridinomitosene has displayed DNA cross-link formation under aerobic, non-reductive conditions and this activity is considered exclusive among mitosenes. We will further investigate DNA/protein activity by treating DNA with a combination cell proteins, that will potentially act as a nucleophile towards any electrophilic sites present in the aziridinomitosene compound. The proposed experiments will advance our knowledge of cell/aziridinomitosene interactions, provide insight into the hypothetical mechanism by which aziridinomitosenes are proposed to cross-link DNA and/or protein, and assist in the development of a more effective cancer-targeting pathway.
Synthesis of C6/C7 Dimethyl Aziridinomitosene Analog for the Analysis of DNA-Protein Crosslink Formation
Aziridinomitosenes are synthetic derivatives of the antitumoral/antibiotic drug mitomycin C, a compound that has been implemented in chemotherapy regimens to treat a variety of cancers over the last few decades. Mitomycin C and Aziridinomitosenes both have a distinct quinone-based chemical structure that facilitates their formation of sequence-specific, cytotoxic DNA interstrand cross-links. Quinone-based drugs, including mitomycin C, have traditionally required a hypoxic environment and reductive activation to form DNA lesions. But recent studies have shown that an unsubstituted aziridinomitosene has displayed DNA cross-link formation under aerobic, non-reductive conditions and this activity is considered exclusive among mitosenes. We will further investigate DNA/protein activity by treating DNA with a combination cell proteins, that will potentially act as a nucleophile towards any electrophilic sites present in the aziridinomitosene compound. The proposed experiments will advance our knowledge of cell/aziridinomitosene interactions, provide insight into the hypothetical mechanism by which aziridinomitosenes are proposed to cross-link DNA and/or protein, and assist in the development of a more effective cancer-targeting pathway.