Synthesis and biosynthesis of a number of biologically active natural products derived from marine macroorganisms and terrestrial microorganisms will be studied. The didemnins (including didemnin B, currently in clinical trials) will be modified chemically by incorporating stereoisomers of isostatine as well as other amino acids in the ring, by altering side chain length, and by replacing ester groups by amides. They will also be studied biosynthetically as either cyanobacterial (symbiont) or tunicate products. Similar studies (both synthetic and biosynthetic) will be carried out with the eudistomins, exceedingly potent antiviral agents. Synthetic and biosynthetic investigations will also be carried out with nodularin and the microcystins, potent hepatotoxins from the cyanobacteria Nodularia spumigena and Microcystis aeruginosa. Biosynthetic attention will be directed toward Adda, the C20B- amino acid component of the toxins. Synthesis of methanofuran, the first coenzyme in methanogenesis, will be completed. Biosynthetic studies will be directed toward the aminocyclitol antibiotics validamycin (employed commercially for sheath blight disease in rice) fortimicin (with a 1,4-diaminocyclitol unit), and neomycin (for in vivo 13C NMR studies); toward the reverse transcriptase inhibitor geldanamycin and the DNA inhibitor pactamycin (for the mutasynthetic incorporation of subunits by idiotrophs and for an in vivo NMR study of geldanamycin); toward berninamycin (for 13C studies involving [13C]serine, threonine, valine, and alpha-aminoadipic acid); toward the crown gall disease biocontrol agent agrocin 84 (for determination or confirmation of its structure and demonstration of precursor incorporations); and toward bromotyrosine metabolites of the sponge Aplysina fistularis (for completion of the biosynthetic pathway).