Frederick C. Seaman

31P-NMR AS A PROBE FOR DRUG-NUCLEIC ACID INTERACTIONS

The structural impact of covalent and noncovalent interactions of drugs with DNA is an important component for understanding the biochemical and biological consequences of DNA damage. Work in this laboratory has focused on a number of potentially therapeutically important drugs that distort DNA by unwinding, bending DNA into the major or minor groove. These lead to enhanced recognition of DNA by proteins involved in transcription and replication. In this paper, we will present the structures of one of these complexes and show how 31P-NMR can be used to monitor these distortive effects.

Molecular Recognition of DNA by Ecteinascidin 743

The Ecteinascidins (Ets; Rinehart et al. 1990), extremely potent antitumor agents isolated from extracts of the marine tunicate Ecteinascidia turbinata, exhibit promising efficacy in several human xenograft models in mice (Sakai et al. 1992, 1996). Their structural novelty prompted researchers to isolate new Et analogs (Sakai et al. 1996), determine the structure (Guan et al. 1993) and absolute configuration of several Ets (Sakai et al. 1996), and complete the total synthesis of Et 743 (1) (Corey et al. 1996). The first Et to advance to clinical trials is 1 (Sakai et al. 1996); however, the mechanism of antitumor activity remains unclear. Bioassays using purified Ets demonstrated inhibitory activity toward DNA and RNA polymerases (Sakai et al. 1996). Sequence-selective high-affinity binding of 1 to duplex DNA (Pommier et al. 1996) suggests a mechanism of action involving DNA interactions. Additionally, the reactive carbinolamine of 1 is analogous to that found in known guanine N2 (GN2) DNA alkylating agents (Remers and Iyengar 1995). The DNA-reactive saframycins (2) are structurally similar to the A and B units of 1, and based on this similarity theoretical models of 1 bound to DNA have been proposed (Guan et al. 1993).