| Cancer, which is a group of more than 100 diseases, presently will strike one out of every four Americans during their lifetimes. As a mode of cancer treatment, chemotherapy will advance only with the development of anti-cancer drugs which have improved preferential cytotoxic actions against neoplastic cells versus normal cells, since unfavorable pharmacodynamic events (drug-plasma protein binding, biodistribution, transport, metabolism, etc.) presently limit the efficacy of most clinically used agents.;The lysoliponucleotide analogs were synthesized by coupling respective nucleotides to linoleyl phosphate; the phosphate was synthesized by reaction of linoleyl alcohol with bis (2,2,2-trichloroethyl)phosphorochloridate followed by removal of the protecting groups. Each nucleotide morpholidate was synthesized in two steps from the corresponding nucleosides. Selective phosphorylation of a given nucleoside gave the nucleoside 5'-phosphate, from which the nucleoside 5'-phosphomorpholidate was prepared; the nucleoside 5'-phosphomorpholidates then were coupled with linoleyl phosphate to produce the desired lysoliponucleotide analog. Established was the identification of two salt forms of the nucleoside 5'-phosphomorpholidates, commonly used synthetic intermediates for liponucleotide and nucleoside polyphosphate syntheses, and the development of a two-step synthesis for unsaturated fatty alkyl phosphates and possibly other lipid classes, such as phosphatidic acids. The lysoliponucleotide analogs synthesized in this investigation are uniquely water soluble and may actually have a more favorable balance between lipid and water solubility when compared to conventional liponucleotides. The lysoliponucleotide analogs are currently being evaluated for anticancer activity.;This dissertation describes the design, rationale, and synthesis of a new class of antimetabolite anticancer agents, lysoliponucleotide analogs (fatty alkyl phosphate-nucleotide conjugates), represented by: 1-(beta)-D-arabino-furanosylcytosine 5'- P'- (Z,Z)-9,12-octadecadienyl dihydrogen pyrophosphate ; 2-amino-9-(beta)-D-ribofuranosyl-9H-purine-6-thiol 5'- P- (Z,Z)-9,12-octadecadienyl dihydrogen pyrophosphate ; and 9-(beta)-D-arabinofuranosyladenine 5'- P'- (Z,Z)-9,12-octadecadienyl hydrogen pyrophosphate . Also described is work relating to the development of non-hydrolyzable phosphonoliponucleotide analogs designed to interfere with the metabolism of natural liponucleotides and to disrupt phospholipid and membrane biosynthesis, an approach to cell kill that is different from reported cytotoxic mechanisms. |
