Abstract

Interstrand cross-links can be introduced into DNA as a consequence of chemotherapy. These lesions are considered to be therapeutically relevant and responsible for the efficacy of bifunctional alkylating agents in cancer chemotherapy. There is considerable evidence that indicates interstrand cross-links are recognized by cells and that this recognition can either mediate repair of damage and survival, or accelerate cell death. Development of tumors resistant to these agents is an important factor in the lack of response by some patients to therapy with these agents. Relatively little is known about the mechanism by which interstrand cross-links are recognized and repaired. In order to investigate repair mechanisms, interstrand cross-linked DNA substrates of well defined structure are required. Such substrates are challenging to prepare in quantities sufficient for biochemical and biophysical studies. A method to synthesize a chemically stable analog of the clinically relevant N7G-alkyl-N7G cross-link was explored. This structural analogue links the C7 atoms of two molecules of 7-iodo-7-deaza-2'-deoxyguanosine with an alkyldiyne linker to form a dimer via the Sonogashira reaction. Several nucleoside dimers were produced using this strategy as proof of principle that it could be employed in the synthesis of interstrand cross-linked DNA. However, in addition to the desired cross-coupling reaction it would appear that a copper catalyzed homocoupling side reaction can also occur