Characterization of new processes for the molecular recognition and chemical modification of DNA is important to a variety of scientific fields including medicinal chemistry, toxicology, and biotechnology. In this regard the natural product leinamycin is of special interest because it efficiently damages DNA by chemical mechanisms that have not been seen previously. When leinamycin encounters a thiol-rich environment such as that found inside cells, the natural product is converted to a DNA-alkylating episulfonium ion via unique sequence of reactions. Importantly, the unusual chemical properties of leinamycin endow the compound with extremely potent cytotoxic properties (IC-50 values of 0.014 micrograms/mL - this translates to an IC-50 of 27 nM). We believe that continued study of leinamycin will reveal new, fundamentally important concepts regarding the diverse ways that mutagens, toxins, and anticancer agents can interact with DNA. The proposed experiments are designed to examine properties of leinamycin that are central to its efficient DNA-alkylating properties, but which are currently not well understood. The work is divided into Four Specific Aims:
Aim 1, Characterize noncovalent interactions of leinamycin with DNA. These studies are of interest because leinamycin associates noncovalently with DNA but does not possess any structural elements typically associated with this property.
Aim 2. Examine whether efficient DNA alkylation by the leinamycin-derived episulfonium ion is made possible by neighboring-group stabilization provided by the C8-alcohol group of the antibiotic. These studies may reveal structural features necessary for the efficient delivery of episulfonium ion alkylating agents through the cellular mileau to DNA.
Aim 3. Investigate whether leinamycin is a reversible DNA-alkylating agent. This unusual property may allow the equilibration or """"""""shuffling"""""""" of DNA adducts to thermodynamically favored sites.
Aim 4. Investigate factors that control the stability of leinamycin's 1,2-dithiolan-3-one-1-oxide """"""""triggering device"""""""". This unique structural unit in leinamycin serves to initiate conversion of the natural product to an alkylating agent upon entering a thiol-rich environment. We plan to identify functional groups in leinamycin that stabilize this inherently fragile heterocycle.
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