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 cytotoxic marine natural product ilimaquinone. The structure of the new compound, called glycinylilimaquinone (91) was determined by spectral methods and by partial synthesis. Compound 91 was also found to be cytotoxic (eg. HCT-116, IC50 = 7.8)µg/mL) and evaluated against the P388 murine lukemia model in vivo, but at a maximally tolerated dose showed no anti-tumor activity. Also described are stucture-activity relationships for some ilimaquinone analogs tested for Golgi vessiculation and microtubule depolymerization in rat kidney cells.