The principal investigator notes that the overall objective of this renewal program involves the use of novel thio- reagents for the synthesis of heterocyclic fused-ring systems and that emphasis is placed on the cyclization and cycloaddition chemistry of sulfonyl and thio- substituted alkenes for the construction of a variety of biologically interesting molecules. Among the reactions to be studied are cycloadditions of bis(phenylsulfonyl)-substituted dienes, isomunchnones, 1,4-dipoles, and other thio-reagents. The project is to focus on the use of alkenyl substituted cyclic thioamides as precursors for mesoionic dipoles. It is also intended to emply cyclic thioamides as precursors to cross-conjugated heterocyclic betaines. The intramolecular 1,4- dipolar cycloaddition reaction of these betaines is to allow the rapid assembly of the basic core unit of a number of alkaloids. In addition, N-acetoacetylated carboxamides are to be utilized to generate the equivalent of a 1,4-dipole and their application for the synthesis of novel heterocycles is to be examined. Finally, the amido- Pummerer- Diels-Alder reaction sequence is to be employed as a method to prepare fused heterocyclic ring compounds. The principal investigator notes that because of their extreme toxicity and consequent low therapeutic index, it seems reasonable to him to modify the basic skeletons of different alkaloids so as to reduce their cytotoxicity without compromising antitumor activity. His intention is to synthesize a variety of unusual fused ring heterocycles so as to evaluate their DNA cleaving abilities. It is indicated that the chemistry to be developed will facilitate the synthesis of antitumor agents and provide quantities of material needed for detailed biological assay. It is noted that many of the substances to be synthesized are expected to show interesting malignant-growth inhibiting properties and will be tested at the National Cancer Institute anticancer screening program. The principal investigator finally notes that generation of biologically-active compounds by synthesis remains an important part of both health related and chemical research.