SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

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DESCRIPTION: This proposal consists of six unrelated synthetic projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs. In the first project the PI plans to complete synthetic studies of the tricyclic guanidine containing batzelladines. The batzelladines are closely related to the crambines and ptilomycalin A, the subject of the previous proposal, and show anti-AIDS activity inhibiting HIV gp 120-Human CD4 binding. In the second project the PI plans to prepare martinelline (112) and martinellic acid (113), structurally novel reduced pyrroloquinolines that are also unusual in possessing two or three guanidines. Martinelline is an effective inhibitor at several G-protein coupled receptor systems (IC50 60-250nM) and may therefore play a role in analgesia and reduction of inflammation. In the third project the PI plans to synthesize rhopaloic acid A (143) a fairly simple nor-sesterterpene which is of considerable interest because it is cytotoxic against myeloid K-562 cells, human Molt-4 leukemia cells and murine L1210 leukemia cells in the 40-100 nM range. Since only 3.1 mg of this compound was isolated from a sponge, total synthesis will be necessary for further investigation of biological activity. The PI has recently completed a synthesis of ent-fumiquinazoline G (162). In the fourth project, he plans to extend this work to prepare fumiquinazoline B (147) and C (151), and spiroquinazoline (152). These compounds are moderately cytotoxic and 152 inhibits the binding of substance P to human U-373 MG intact cells and therefore might be a novel analgesic or antiinflammatory agent. FR901483 (186) is an unusual tyrosine dimer with an azabicyclo (3.3.1) nonane skeleton that exerts potent immunosuppressive activity in vitro and significantly prolongs survival time in the rat skin allograft model. In preliminary studies, the PI has developed a two step route to 179, which contains the suitably functionalized complete carbon skeleton of 186. In the sixth project the PI plans to prepare penostatins A (188), B (189), and C (187) which were isolated last year and shown to be cytotoxic to P388 leukemia at 0.8-1.1 mg/mL. The key step in this synthesis is the intramolecular Diels-Alder reaction of trienyl glyoxylate 192 to give 191 and stereoisomers.