SYNTHESIS OF ANTITUMOR NATURAL PRODUCTS

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DESCRIPTION: It is stated that the long term goals of this project involve the development of new chemistry to be used in synthesis as well as in the preparation of target structures for the purposes of investigating their biological activity and modes of action. The focus in terms of biological profile in this program is to center on three types of agents. It is noted that the first is a group of cytotoxic natural products. The PI indicates that selectivity of such systems would reside in the enhanced vulnerability of rapidly dividing cells to the various actions of cytotoxic agents and that in this category, he will be addressing synthetic, mechanistic, and SAR issues related to (A) taxol, (B) the epothilones, (C) enediyne related hybrids, (D) ET-743, and (E) camptothecin. He notes that his attentions will also be directed to cytotoxic agents known to be implicated in cell cycle modulation and that these goal structures include (F) radicicol, (G) herbimycin, (H) xestocyclamine, and (I) tryprostatin. The PI indicates that in addition, he hopes to be following up some dramatic leads in the area of agents which might potentially reverse the multidrug resistance (MDR) phenotype and that compounds in this class include (J) the ardeemins, and (K) the gypsetins, as well as related pyrolo indole based natural products. He reports that another natural product target, CP 225,917 (L) poses a difficult and attractive structure given reports that it is a farnesyl transferase inhibitor. The third area is to involve the synthesis of fully synthetic antitumor antigens. The PI notes that the concept involves previous observations that novel carbohydrate patterns are expressed at the cell surface of transformed cells and that these tend to be bound to the cell membrane, either through involvement as glycoproteins, or as glycolipids. He states that the thought is that synthetic versions of these tumor antigens might elicit an immune response leading to antibody formation, complement fixation and cell lysis and that minimally, such tumor antigens could be used in very early diagnosis as a devise for early screening of antibody formation. It is noted that the tumor antigens which will be addressed are (M) a breast tumor antigen, (N) a gastric tumor antigen, and (O) a colon cancer antigen. In the area of chemical methodology, the PI is to explore in some detail, the scope of transition metal mediated furanylation reactions, new strategies in ring construction, new departures in diastereoselective and enantioselective synthesis and the synthesis of neoglycoconjugates including neoglycoproteins.