The overall objectives of the proposed research are (1) to determine the structure of drug-DNA adducts, explore the molecular mechanisms for sequence recognition of covalently modifying DNA reactive drugs, and use this information to guide the design and synthesis of novel DNA reactive compounds and (20 use ternary complexes (drug-DNA-protein) as a basis to understand the biochemical and biological effects of drug modification of DNA. Objectives one and two are related. Objective one asks how the sequence specificity is achieved, while objective two asks why Nature has evolved a complex natural product to target these particular sequences. To address why, we need to know the structural significance of the drug-modified sequence and its relationship to the biochemical and biological consequences. The specific objectives of the proposed research are to: (1) define the structures of various drug-DNA adducts using high-field NMR and molecular modeling and continue our work to define the molecular mechanisms for sequence recognition of DNA by monoalkylation and cross- linking compounds. (2) use DNA reactive drugs with well-characterized effects on DNA structure as molecular probes for protein-DNA interactions. (3) define protein-DNA complexes as receptors for drug actions. (4) continue our efforts to use a template-directed approach to the design of novel DNA interactive compounds having unique mechanisms of action. Two groups of antitumor agents are the major focus of this proposal: the pyrrolo(1,4)benzodiazepines [P(1,4)Bs] and cyclopropylindoles (CPIs) and their respective cross-linkers. Within the CPI group, adozelesin is in phase I and phase II clinical trials; carzelesin, a prodrug of another monoalkylating CPI, is in phase I trials in Europe; and bizelesin should enter phase I trials in 1993. While the full clinical potential of these compounds is still to be appreciated, the initial clinical trials show promising activity with documented responses in patients with breast and gastric cancer, melanoma, and leukemia.
| Hurley, L H (1989) DNA and associated targets for drug design. J Med Chem 32:2027-33 |
