The goals of this program are to study the interaction of the clinically relevant antitumor antibiotics, including FR900482, FR66979 and several synthetic compounds with DNA interstrand cross-linking ability, with cellular nucleic acids and DNA-binding proteins at the molecular level. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. A new class of antitumor pro-drugs, that can be selectively activated by chemical or photochemical means will be synthesized and their interaction with cellular nucleic acids and DNA-binding proteins will be studied. During the coming funding cycle, we plan to address the following objectives: (1) Synthetic methodology developed during the current funding cycle will be utilized to complete an efficient asymmetric, stereocontrolled total synthesis of FR900482 (1) and FR66979 (2). (2) The synthetic methodology we have developed in the total synthesis endeavor shall be utilized to prepare mitosene progenitors based on the FR900482 structure, that can be triggered by alternative chemical and biochemical means. (3) The interaction of FK973 with DNA complexed to several DNA-binding proteins that associate with DNA in the minor groove will be examined in detail. DNA substrates will be constructed and incubated with the respective peptide binding domains (BD) of the High Mobility Group I/Y (HMG-I/Y) DNA-binding proteins in the presence of FR66979*; subsequent enzymatic digestion of the cross-linked nucleotide-drug-amino acid adduct will be examined to isolate and fully characterize the structure of the covalent cross-link. (4) DNA cross-linking studies with full-length DNA-binding proteins of the High Mobility Group I/Y (HMG-I/Y) will be conducted with several synthetic DNA substrates. (5) In collaboration with Prof. Raymond Reeves (Washington State University), we plan to examine the DNA-protein cross-linking capacity of FR66979 in vivo in neoplastically transformed cells. (6) A new class of """"""""latent"""""""" triggerable progenitors of mitosenes, pyrrolizidine alkaloids and substances related to the anthramycins will be synthesized and utilized as potential new anti-cancer drugs and probes for the macromolecular cross-links.
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