Sidney Hecht, PhD
Synthesis and characterization of antitumor agents
Research in the area of organic chemistry is focused on the synthesis of bleomycin group antibiotics; members of this family are used clinically as antitumor agents. The total synthesis of bleomycin A2 was achieved in our laboratory some time ago; at present we are synthesizing tallysomycin S2B, a naturally occurring antitumor agent of somewhat more complex structure than bleomycin itself. Synthetic challenges within this structure include two asymmetric centers of undefined absolute configuration, and an unusual glycosylcarbinolamide functionality.
By the use of synthetic bleomycin analogues, the way in which bleomycin works as an antitumor agent is also under study. This mechanism involves the sequence-selective degradation of DNA by an oxidative process; RNA is also degraded and this may constitute a second therapeutic locus for the drug. In an effort to identify bleomycin analogues that cleave RNA specifically, we have prepared bleomycin by solid phase synthesis and are now making bleomycin combinatorial libraries. It should be possible to select the bleomycins of interest from these libraries.
Another biochemical locus of interest is DNA topoisomerase I, an enzyme that effects the relaxation of supercoiled DNA by the transient, reversible nicking of one strand of the DNA duplex. The enzyme-DNA complex, which is a covalent binary complex in which the active site tyrosine OH group is attached to the DNA via a phosphate diester linkage, is the key intermediate that permits DNA relaxation. We discovered that the antitumor agent camptothecin serves to stabilize the enzyme-DNA binary complex, and thereby prevents actively growing populations of cells from utilizing their DNA for replication and transcription. The camptothecin analogue topotecan, in whose discovery we participated, is presently marketed by SmithKline Beecham Pharmaceuticals under the tradename Hycamtin for the treatment of ovarian cancer and small cell lung cancer.
Research interests in the area of protein biosynthesis involve a description of the molecular mechanisms of the partial reactions of protein biosynthesis, as well as the use of "chemically misacylated" tRNA's in protein biosynthesizing systems to produce polypeptides having synthetic amino acids at predetermined positions. Presently, we are studying structural analogues of the enzymes dihydrofolate reductase and HIV-1 protease bearing synthetic amino acids at key positions that can help to define important mechanistic elements of enzyme function. We have also demonstrated that a hydrazino amino acid can participate in peptide bond formation; both N atoms appear to be capable of acting as nucleophiles in the peptide bond-forming reaction.
Another initiative has involved the identification of natural products that inhibit DNA polymerase ß. This enzyme repairs the DNA damage inflicted on DNA in tumor cells by antitumor agents such as bleomycin and cis-platin. Inhibitors may block this repair and thereby potentiate the action of therapeutically employed DNA damaging agents. Thus far, we have identified several types of naturally occurring inhibitors, characterized the nature of their enzyme inhibition, and shown in cell culture that they potentiate the action of bleomycin and cis-platin, and also block unscheduled DNA synthesis induced by these agents.