The research we describe in this proposal is designed to elucidate the mechanism by which 1,3-dioxo-1,2-dithiolanes related to antitumor antibiotic leinamycin (1) cleave deoxyribonucleic acid (DNA). In vitro experiments showed that DNA-cleavage by LM is triggered by added thiol, but does not involve radicals. Importantly, it was found that S- deoxyleinamycin (2) displays no biological activity and does not cleave DNA in in vitro experiments. Thus, it appears that the unusual ,3-dioxo-1, 2- dithiolane ring (3) is required for DNA-cleavage by LM. At this time, the chemical mechanism of DNA cleavage by LM is completely unknown and no detailed proposals for this chemistry have been made. In this proposal we suggest general mechanisms for the cleavage of DNA by 1,3-dioxo-1,2- dithiolanes. In our preliminary work, we have identified simple, synthetic 1,3-dioxo- 1,2-dithiolanes that, like leinamycin, cleave DNA in a thiol-dependent manner. The work we describe herein has three main goals; we will (1) investigate the structural requirements for DNA cleavage by dioxodithiolanes, (2) determine the chemical mechanism by which dioxodithiolanes cleave DNA, (3) design and synthesize novel thiol- triggered DNA-cleaving agents that utilize the dioxodiathiolane """"""""core"""""""". In order to meet these goals, we will synthesize a series of analogs in which we systematically alter the functionality on the dioxodithiolane ring system. We will produce evidence for (or against) our proposed mechanisms by studying athe reactivity of these analogs with DNA and in chemical model reactions. We plan to apply the information that we gain regarding the cleavage of DNA by dioxodithiolanes toward the design of novel DNA-cleaving agents that combine this DNA-cleaving functional group with a DNA-binding moiety of known affinity and specificity. We fell that the chemical mechanism by which 1,3-dioxo-1,2-dithiolanes cleave DNA is of particular interest, because dioxodithiolanes appear to be a new chemical class of DNA-cleaving agents.
