STRUCTURE AND FUNCTION OF ANTITUMOR DRUG ACTINOMYCIN D. Fusao Takusagawa, Shigehiro Kamitori, Miho Shinomiya, Wenhua Chu, Robert F. Weaver, Departments of Chemistry and Biochemistry, University of Kansas, Lawrence, KS 66045-0046

A group of compounds called intercalators bind intercalatively to DNA, and interrupt RNA synthesis (transcription) and/or DNA synthesis (replication). Some intercalators have been used as anticancer drugs and others are carcinogens. There are several important questions to be answered in order to understand the biological activities of useful intercalators. Some of the questions are: how intercalators bind to DNA, how intercalators distort DNA structures, and how intercalators recognize their binding sequence. Three-dimensional structures of DNA drug complexes, in which a drug intercalates between the middle base pairs of a relatively long DNA fragment, has been sought as a more practical model for biological systems.

Actinomycin D (AMD) is known to bind intercalatively on DNA and severely inhibits RNA ploymerase activity. It has been employed clinically as an antitumor agent for treat of highly malignant tumors. However, its selective toxicity is poor because it is an extremely potent, specific inhibitor of DNA-directed RNA synthesis. Recently, we have determined the three crystal structures of the complexes between d(GAAGCTTC)₂ and AMD and its analogues, in which AMD intercalated between the middle 5'-GC-3' base pairs (Kamitori, et al, JMB, 225, 445 (1992); Kamitori, et al., JACS, 116, 4154 (1994); Shinomiya, et. al., Biochemistry, 34, 8481 (1995)). These crystal structures of the complexes show how the drug interacts with DNA. On the basis of the structures, we have synthesized series of AMD analogues and characterized the physical and biological properties. At the meeting, the structure and activity relationship will be discussed.