As a class, amides are of great interest in biological studies and pharmaceutical application. In this work, podocarpic acid, a natural tricyclic diterpene, derived from Podocarpus species, has been employed to form a novel family of amide derivatives which will later be studied for their potential as new drug leads. Novel amide derivatives of podocarpic acid were synthesized from podocarpic acid in three steps. The first step involved methylation with dimethylsulfate to form methyl-O-methylpodocarpate. This step was followed by iodination with iodine to give iodomethyl-O-methylpodocarpate. Finally amidation with various aliphatic amides using a copper catalyst yielded four amide derivatives of podocarpic acid. However, iodomethyl-O-methylpodocarpate did not react with aromatic amides. This is perhaps because of the reduction in electrophilicity of an aromatic amide versus an aliphatic amide. Thus this research had led to the discovery of a method that is selective for the synthesis of aliphatic amide derivatives of podocarpic acid. Furthermore, five novel derivatives of podocarpic acid have been synthesized. Therefore a small library of novel compounds has been synthesized by utilizing selective methodology, that are now available for future examination of their anticancer and anti-tuberculosis properties.

The goal of part I of this thesis was to isolate pure anti cancer compounds from the Russian plant Sanguisorba officinalis. This plant was selected for investigation because it showed 100% activity against leukemia (L1210 mouse leukemia cells) during the preliminary screening of approximately 100 Russian plant extracts. This work has resulted in the isolation of novel compound 11 using traditional chromatography techniques. Compound 11 was characterized with spectroscopic techniques such as IR, 1H NMR, 13C NMR, DEPT, DQCOSY and MS. Compound 11 was assigned the structure dipentyl 2-(4-(pentan-3-yl) phenyl) malonate. The goal of part II of this thesis was to synthesize novel ethers of podocarpic acid. Ethers are of great interest in biological studies and pharmaceutical applications because of their wide variety of uses in the treatment of various diseases. A novel family of ether derivatives was synthesized using podocarpic acid (a natural tricyclic diterpene derived from podocarpus species) as a template. Novel ether derivatives of podocarpic acid were synthesized from podocarpic acid in three steps. The first step involved methylation of podocarpic acid with dimethyl sulfate to form methyl-o-methyl podocarpate. The second step was iodination of methyl-o-methyl podocarpate with iodine in presence of a mercury catalyst to form 13-iodo methyl-o-methyl podocarpate. This was followed by formation of novel aliphatic ethers using a copper catalyst. Thus this research had led to the discovery of new methodology for synthesis of three novel aliphatic ether derivatives of podocarpic acid. These ethers will be tested for their biological activity against various types of cancer, tuberculosis by National Institutes of Health.

<p> The C-B-A ring formation sequence has been adopted towards a total synthesis of podocarpic acid starting from 2, 7-dihydroxynaphthalene. Experimental procedures which were developed by other workers have been modified to improve the yields and the purity of the products. </p> <p> Using naturally occurring podocarpic acid, a reliable procedure has been explored for the functionalization of C-6 and C-7 positions in order to construct the 19,6-lactone ring in synthetically satisfactory yields. Catalytic reduction of the aromatic ring C, after functionalization of ring B, has been investigated with the aim of developing a pathway towards the elaboration of the C, D ring system of the kaurane skeleton. </p> / Thesis / Doctor of Philosophy (PhD)

Podocarpic acid (a diterpenoid resin acid extracted from the Podocarpacea specie of plants) has shown cytotoxicity against carcinoma of the nasopharynx. Since this discovery has been made, research has been performed in order to alter the structure of the resin acid so as to increase the anticancer activity. The carboxylic acid and phenol functional groups, which are present in podocarpic acid, make it possible to synthesize new derivatives selectively at the C-15, C-13, and C-7 positions as well as by substitution of the phenol hydroxyl group. Thus numerous derivatives can be prepared, in high yield, for the purpose of investigating their potential, as new drug leads for the treatment of cancer. In this study, Doyle's catalyst (Dirhodium tetrakis caprolactamate) was used to form a novel derivative in high yield (85%) which contained a 3-membered aziridine ring at the C-6 and C-7 position. The main thrust of this research involved the formation a series of novel derivatives of the aziridine compound by utilizing phenol and m-chlorophenol as nucleophiles to open the aziridine ring. These novel compounds will now be sent to the National Institute of Health (NIH) for bioassay against 60 human cancer cell lines.