Electronic Theses and Dissertations

Date of Award

2011

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Mitchell A. Avery

Second Advisor

Takashi Tomioka

Third Advisor

John S. Williamson

Abstract

Part A: Studies towards total synthesis of an antifungal and anticancer agent, Pseudolaric acid B. Marked by the uncontrolled cell proliferation, cancer is one of the deadliest diseases, accounting for about 7.0 million deaths in 2007. Cancer is second leading cause of death worldwide, according to the American Cancer Society. Cancer chemotherapy has evolved through many years of painstaking research, and as a result, today we are able to cure at least some of cancers. One of the major impediments in the development of new drugs for treating cancer is that most of the approved drugs are themselves toxic and produce drug resistance during the initial exposure of these drugs. Thus there is a continued need to search for new/better drugs. Over the years, numerous natural products have been identified as leads for the drug discovery and development process. Some of the most well-known examples are Taxol, vincristine, vinblastine, Camptothecin and Etoposide. Pseudolaric acid B is a diterpenoidal natural product isolated from the extract of the root bark of Pseudolarix kaempferi, is a Chinese herbal medicine called Tu Jin Pi, which has been used for many years against fungal infections of the skin and nails. Studies of the bark of this plant have led to the isolation of several novel diterpene acids, namely pseudolaric acids A (PLAA, 1), B (PLAB, 2), C (PLAC, 3) and B-Glycoside (PLAB-Gly, 4)4-6. We hereby report our studies towards the synthesis of PLAB using a model substrate. We have accomplished the synthesis of the model system, which can now be applied to the total synthesis of PLAB. Key steps of our approach include Lewis acid mediated Diels Alder (DA) cycloaddition to give a bicyclo [2.2.2] acid, and a cationic 1,2- rearrangement. Series of functional group transformation reactions of the DA adduct, epoxidation, a tandem ring-opening-ring closing event, decarboxylation, and an enhanced Wagner-Meerwein rearrangement afforded a bicyclo [3.2.1] core 3.22. Unfortunately, X-ray analyses of the bicyclo derivative revealed an inverted relative configuration. All the approaches to solving this end stage problem will be presented in the dissertation. Finally, we were able to obtain the crucial intermediate 3.22, with the desired relative stereochemistry. With this intermediate in hand we have started efforts to complete the total synthesis of PLAB. Part B: Synthesis and biological evaluation of Berkeleyamide A and its derivatives. Interleukin-1? converting enzyme (ICE), also known as caspase-1, responsible for the cleavage and activation of interleukin-1? (IL-1?) to its active form (17K), is involved in the pathogenesis of several auto immune inflammatory disorders. Subsequent research over the years suggests that ICE plays a pivotal role in regulation of proinflammatory cytokines and its inhibition can be a potential therapeutic target for the treatment of immune-mediated inflammatory diseases. Recently several interesting secondary metabolites have been isolated from the rare microbes evolved in extreme ecosystems such as a Berkeley Pit Lake in search of potential anticancer and antimicrobial agents. One such natural product, Berkeleyamide A, isolated from the fungi Pencillium rubrum, inhibited caspase-1 (ICE) and the signal transducing enzyme matrix metalloproteinase-3 (MMP-3) in a low micromolar range. Herein we report an efficient total synthesis of (-)-berkeleyamide A. The total synthesis was accomplished in overall 18% yield, starting from N-Boc- L-leucinal, employing Evans' syn-aldol reaction of N-acyl-4 R-benzyl oxazolidin-2-one as the key step. Excellent enantioselectivity (more than 95% ee) was obtained with a good yield (75%) for the crucial C-C bond formation key reaction step. In summary, our synthetic endeavor of (-)-berkeleyamide A is very efficient, scalable and highly diastereoselective with the flexibility to develop various analogues of the natural product. Using this modular approach, we accomplished syntheses of four other diastereomers. We have also carried out molecular docking studies to predict the binding mode of berkeleyamide A in the ICE active site. Furthermore, we designed a library of compounds as potential caspase-1 inhibitors based on berkeleymide A scaffold. Finally we carried out biological evaluation of Berkeleyamide A and its dervivatives. We tested these compounds for caspase-1 inhibition, antfungal, antimalarial, antileishmanial and cytotoxic activities. However, berkeleyamide A and its derivatives failed to show promise in any of these assays.

Concentration/Emphasis

Pharmaceutics

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