Thesis (M.S.)--Lehigh University, 2009. / Adviser: Robert A. Flowers.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 88-90).

Thesis (Ph. D.)--University of California, San Francisco with the University of California, Berkeley, 2008. / Source: Dissertation Abstracts International, Volume: 69-12, Section: B, page: 7645. Adviser: Francis C. Szoka.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 71-02, Section: B, page: . Adviser: Brian K. Shoichet.

Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3813. Adviser: Eric Oldfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Since tuberculosis incidence has been increasing world-wide due, in part, to infection from drug-resistant strains of Mycobacterium tuberculosis, there is a need for new, more effective drugs for treatment (Bloom and Murray 1992). To this end, the strategies of medicinal chemistry were applied this problem and a group of 22 small organic molecules were prepared as inhibitors of mycobacterial growth. The group is comprised of pyridines and pyrazines, boronic acids and esters, and diazaborines. The 10 pyridine and pyrazine compounds are composed of 5 pyridine derivatives (3PYSO, 4PYSO, 3PYS, 4PYS, 3PYA) including 3 unreported (3PYS, 4PYS, 3PYA), and 5 pyrazine derivatives (PZSO, PZS, POAH, PZUREA, PZCS) including 2 unreported (PZUREA, PZCS). These 10 compounds have a rationale for antimycobacterial activity that involves mycobacterial penetration, then bioactivation by enzyme systems known to exists in mycobacteria to metabolites expected to be toxic to the organism. The 6 boronic acids and esters are composed of 3 boronic acids (3PYB, 4PYB, NPBA) and 3 boronic acid esters (NPOB, DEPYB, BDPYB), with BDPYB unreported. The compounds were expected to have antimycobacterial activity due to the ability of boron to form charged, reversible tetrahedral complexes and compete for enzyme active-sites. Since diazaborines were shown to inhibit bacterial growth by a novel mechanism, 6 benzodiazaborines were also synthesized, composed of 2 [2,3,1] -benzo-e-diazaborines (SDZB, PDZB) and 4 new [2,4,1] -benzo-e-diazaborines (OBDZB, OPDZB, TPDZB, PZDZB; Baldock, Rafferty et al. 1996). In order to prepare aza-analogs of ASDZB and APDZB, a lesser-known synthetic strategy relying on a dilithiated intermediate was used in an attempt of their preparation as well its successful application for SDZB and PDZB (Sharp and Skinner 1986). All of the compounds were then evaluated in vitro for growth inhibition of wild-type M. tuberculosis H₃₇Rᵥ by Dr. Scott G. Franzblau at LSU. Of the compounds tested, the diazaborines were the most active, although much less than one of the best available drugs, isoniazid. The majority of the group had activities comparable to or better than another widely used drug, pyrazinamide.

Cortistatin A, a marine natural product isolated in the mid-2000, was reported as a highly selective and potent anti-angiogenic agent. Based on the known SAR (structure activity relationship) studies of cortistatins and the related synthetic compounds, simplified tricyclic and tetracyclic analogs (3.8, 3.32) resembling cortistatin A were developed and the biological activities were evaluated. Improved cell-growth inhibitory properties were observed after carefully re-designing and synthesizing the analogs with the lessons learned from X-ray crystal structure of cortistatin A bound to the target protein. From the first lead compound 4.65, more than fifty analogs were prepared with different functional groups on the C3 and C17 positions, aided by the readily scalable common intermediate 4.55 from the commercially available estrone in twelve steps with five column purifications. The final lead compound showing both decent potency and stability will be selected in the near future.

In part A, the attempts at synthesizing quaternary centres via radical reactions are described. Using tartrate acetals as chiral auxiliaries, tertiary bromides were submitted to radical allylation conditions in an effort to form 1,3-dicarbonyl compounds 27 possessing an asymmetric quaternary centre at C2.* Part B describes the synthesis of chiral hydrazide 129 and its ability to catalyze the Diels-Alder reaction is examined. The application of chiral hydrazides 131 to the organocatalytic hydride reduction of alpha,beta-unsaturated aldehydes and the alpha-chlorination of aldehydes is also recounted herein.* Finally, in Part C, efforts towards the synthesis of potential broad spectrum HIV-1 reverse transcriptase inhibitors are described. Compounds 161 are based on the TIBO family of compounds and possess a novel alkylaryl appendage.* *Please refer to dissertation for diagrams.

Recently, photocages capable of releasing biologically relevant molecules have been reported, which utilize the rapid and efficient photodecarboxylation of 2-xanthone acetic acid (XAA) with UVA irradiation. This thesis focuses on the development of functionalized xanthonate photocages to be used for surface-tethering applications. Firstly, the preparation of amine and acetamide functionalized xanthonate (and thioxanthonate) photocage precursors will be described. Investigation into the photochemistry of the prepared derivatives led to the discovery of a solvent composition dependence on the photodecarboxylation quantum yield of acetamide derivatives. The photodecarboxylation of these derivatives occurs cleanly in the same way as XAA, but with lower efficiency. The preparation and photochemical study of acetamide functionalized photocages will then be described. Photorelease of acetate and phenylalanine demonstrated the capability of amide functionalized photocages to release biologically relevant molecules. Lastly, initial investigations into polymer tethering will be described. Attempted amide coupling through the aromatic amine led to the attachment of a short chain carboxylic acid terminated linker to modify the linking site.

The synthesis of the taxanes derivatives has been the major focus of this research. The efforts made towards the synthesis of these complex and successful drugs for the treatment of cancer have resulted in the development of efficient synthetic strategies. These approaches have arisen mainly from our studies in the carbometallation of propargyl alcohols and the development of stereoselective Lewis acid catalyzed IMDA. The application of these potential synthetic strategies has yielded very significant results. The synthesis of the tricyclic core of the taxanes (2.149) by a novel carbometallation-cycloaddition-RCM sequence was successfully achieved using readily available starting materials and mild reaction conditions. In addition, the versatile carbometallation-cycloaddition sequence allowed the synthesis of AB ring system of taxanes with different functionalities (2.126, 2.111 and 2.128). The construction of a functionalized A ring (2.84) was also accomplished. This intermediate and some of its derivatives were employed to attempt the synthesis of B ring of taxanes by RCM. Additionally, the further functionalization of AB and ABC ring-systems of taxanes was investigated. Unfortunately, the synthesis of a biological active taxane derivative was not possible. In addition, we have studied the in situ carbonyl addition oxy-Cope rearrangement of unsaturated ketones.* *Please refer to dissertation for diagrams.