It is stated that support is requested to maintain a challenging and highly successful research program investigating fundamental chemical behavior and structure of recently discovered, biologically active natural metabolites. The principal investigator notes that the research plan details an ambitious program which will focus on new synthetic schemes toward important target molecules, offering the opportunity to adapt and extend the knowledge gained from previous successes. He indicates that the fundamental objectives of this proposal go well beyond achieving the specific syntheses and afford basic methodology and novel synthesis strategies as categorized below. It is reported that the rhizoxin antibiotics are currently in clinical evaluation and that they are a unique family of potent antitumor agents which are receiving close attention in chemical and biological studies worldwide and that in fact, these substances or their derivatives have the potential for commercial development in certain chemotherapies. The principal investigator notes that as a result of rapid advances in his synthesis, the proposal will focus on remaining stages for near-term completion and that in addition, new strategies to circumvent problems uncovered in the ongoing effort are described, and new methods to improve the efficiency of his plan to rhizoxins are presented. It is indicated that the amphidinolides are an exciting new class of marine antitumor macrolides which are available in extremely small quantities. It is noted that these substances are among the most potent new antitumor leads recorded in standard NCI cell assays and that IC5o's as low as 0.00014 microg/mL have been reported. The principal investigator states that an expedient synthesis of the 15-membered lactone, amphidinolide J is proposed as a departure point of these efforts and that preliminary studies toward amphidinolide J have been presented. He further notes that a proposal for the preparation of amphidinolide K, a nineteen-membered antitumor macrolide, has been presented. He feels that these molecules provide an extraordinary new lead for chemotherapy and that his research plan describes an efficient route for preparation and details numerous alternatives toward the first synthesis of examples of these substances. The dolabellanes and fusicoccanes are reported to be unique diterpenes which demonstrate a wide variety of biological effects. Many examples are said to display antibacterial and antitumor activities. The principal investigator notes that the fusicoccanes can be derived from the eleven-membered dolabelladienes via transannular cyclizations, as described from his laboratory. He indicates also that further efforts for synthesis of cotylenol, the aglycone of plant growth regulators is based on his preliminary discoveries.
