Anti-Neoplastic Agents of Marine Origin: Identification, Synthesis, and Structure-Activity Studies

This dissertation is divided into three freestanding chapters. Chapter I describes the total synthesis of the cytotoxic marine natural product trans-2,5-bis(6'-bromo-3'­ indolyl)piperazine (1), as well as racemic cis-2,5-bis(6'-bromo-3'-indolyl)piperazine (78). Also described are the syntheses of two additional analogs of the natural product 1; trans-2,5-bis(5'-bromo-3'-indolyl)piperazine (79) and racemic cis-2,5-bis(5'-bromo-3'­ indolyl)piperazine (80). These piperazines were prepared by electophillic addition of the indole to cis-3,6-dibromo-1 ,4-bis(tert-butoxycarbonyl)-2,5-piperazinedione, followed by isomerization and reduction of the resulting 3,6-bis(indolyl)-2,5-piperazinediones with borane-tetrahydrofuran. The piperazine products 1 and 78-80 were all found to be cytotoxic. In collaboration with the National Cancer Institute (NCI), in vivo testing was performed. The piperazine compounds 78, 80 and 1 have been identified as selectively cytotoxic to colon tumors. NCI has detetmined that the maximally tolerated doses in mice of 1 and 78 are 400 and 450 mg/kg, respectively. Efforts are underway to provide more of 1, 78 and 80 for further in vivo testing by the NCI. In addition the piperazine products were found to inhibit phorbol-induced inflammation in the Mouse Ear Edema Assay at levels ranging from 44% for 78, 69% for 80 and 71% for 1 to a maximum of 80% for 79.Chapter 2 describes the isolation and stucture elucidation of the marine natural product (2R, 3R, 10R)-(Z)-2-amino-1,3,10-trihydroxy-11-octadecene (81). The stucture was determined by a combination of spectral analyses and derivatizations. The Modified Mosher Method was used to determine the absolute configurations of C-3 and C-l 0. The compound was determined to possess broad spectrum anti-microbial properties, and was also found to inhibit phorbol-induced inflammation in the Mouse Ear Edema Assay at a level of 43%.Chapter 3 describes the isolation and synthesis of a glycine derivative of the cytotoxi