Peptide ligands represent the most important hormones and neurotransmitters in physiological processes. Although native biologically active peptides have a great potential for medical applications, they often need to be modified to overcome certain inherent problems. A new research area called peptidomimetics has been developed in the last twenty years. The first generation of β-turn mimetics was focused on mimicking the β-turn backbone. In the last decade, many types of bicyclic β-turn dipeptides (BTD) have been design and synthesized. However, these methods do not have straightforward ways to introduce side chain groups on both rings. The introduction of functionalities on BTD, as the second generation of β-turn mimetics, is the major goal of my dissertation. By retrosynthetic analysis, convergent synthetic methodologies were initiated for [5,5]- and [6,5]-BTDs. Two kinds of nonproteinous amino acids are required in the strategies. One is the β-substituted cysteine derivatives and the other is β-substituted ω-unsaturated amino acids. The racemic β-vinylphenylalanine was synthesized by using Kazmaier-Claisen rearrangement, and the ω-unsaturated amino acids and β-substituted δ,ε-unsaturated amino acids were synthesized by using Ni(II)-complexes as chiral auxiliaries. Using these starting materials, [5,5]-BTD analogues were synthesized by a five-step strategy. The synthesis of [6,5]-BTDs has to proceed without formation of the 5-membered hemiaminal, which blocks further reaction. A Nᵅ-TFA protection group was used in this strategy and finally an efficient methodology was developed to generate the side chain groups into [6,5]-BTD analogues in nine steps. During the development of these methods, we solved the challenge to synthesize all 16 or 32 of the possible diastereomeric dipeptide mimetics. A novel idea to solve these problems was to synthesize the targeted peptide mimetics by solid phase methods in a combinatorial fashion, as the third generation of β-turn mimetics. We have succeeded in the synthesis of [3,3,0]-BTD²,³-Leu-enkephalins by unconventional solid phase synthesis, and four analogues have been synthesized and purified. This method is ready to expand to other sizes of BTD and to other target peptides with different functionalities.

Influenza is an enveloped virus, consisting of two surface glycoproteins, neuraminidase and hemagglutinin. The viral receptor is a glycoconjugate on which sialic acid is the terminal sugar. Neuraminidase catalyses the cleavage of the terminal sialic acid from the adjoining carbohydrate moiety, thereby assisting the virus to spread, and infect new cells. Thus development of neuraminidase inhibitors has been of great interest. Our studies are based on synthesis of new potential neuraminidase inhibitors. The synthetic strategy that was adopted for the preparation of the potential inhibitors, required the introduction of glycine ethyl ester at C1 of 1,4-lactone derivatives of N-acetylneuraminic acid. Furthermore, the rate of the ring opening of the 1,4-lactones was studied via proton NMR. Structural determination of the lactones are reported using specialized NMR techniques (Inverse Detected Single Quantum Filtered Long Range Spectroscopy). Conformational studies of the lactones were also determined with computational models.

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The use of immobilized enzymes has steadily increased in recent years. Based upon the advantages that immobilized enzymes possess over soluble enzymes, numerous applications have emerged in medical and analytical fields. This work demonstrates the applicability of a liquid chromatographic system based upon coupled on-line immobilized enzyme reactors (IMERs) to organic synthesis, biochemistry and pharmacology. It is envisioned that the model system will grow into a modular process where synthetic chemists can add or subtract the enzymes necessary for their particular synthetic goal. The system allows for on-line chromatographic purification and structural identification of products and could greatly reduce time required to discover new synthetic pathways. In addition, the construction of a coupled enzyme system provides a number of approaches to basic research into synthetic and metabolic pathways as well as a rapid method for the discovery of new pharmaceutical substances. / A coupled system using extremely different enzymes with incompatible cofactors and reaction conditions has been constructed. The significance of the proposed project not only lies in the development of the liquid chromatographic on-line enzyme cascade but also in the biosynthetic pathway chosen for this study. The biosynthetic pathway involving dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase encompass the synthesis of the key transmitters, norepinephrine and epinephrine. The results demonstrate for the first time the immobilization of dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase. The IMERs are active and can be used in a liquid chromatographic format for qualitative and quantitative determinations. Studies with the IMER-HPLC systems have also shown that the activity of the immobilized enzymes reflects the non-immobilized enzymes. Thus, the IMER-HPLC system can be used to carry out standard Michaelis-Menten enzyme kinetic studies and to quantitatively determine enzyme kinetic constants, identify specific enzyme inhibitors, provide information regarding the mode of inhibition and the inhibitor constants (Ki). The immobilized enzyme reactors used independently or as a combination will provide a unique opportunity to explore the interrelationships between these enzymes, to investigate the source of catecholamine-related disorders and to design new drug entities for identified clinical syndromes.

This study reports a series of promising and structurally diverse potential HIV-1 protease inhibitors. Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). HIV infection disrupts the immune system and makes the body susceptible to opportunistic infections. If untreated, AIDS is generally fatal. Today, AIDS has become a long lasting pandemic. According to the World Health Organization (WHO) and Joint United Nations Program (UNAIDS-2009) report, it is estimated that 33.3 million men, women and children worldwide are infected with HIV. This situation is steadily deteriorating in some parts of the world compared to the previous years. One of the major drawbacks associated with the currently FDA-approved anti-HIV drugs are severe side effects, toxicities, high dosage and high treatment cost. Thus, an urgent need for new drugs to combat HIV is apparent. In the first part of the study, research efforts were focused to synthesize potent pentacycloundecane (PCU) derived peptide and peptoids as protease inhibitors. It is proposed that these inhibitors bind to wild type C-South African HIV protease (C-SA) catalytic site via a non-cleavable or non-hydrolysable cyclic ether bond for the first polycyclic cage compound and via a dihydroxylethelene type functional group for the second cage compound. The desired compounds were synthesized by coupling of the peptides and peptoids to the PCU derived cage. Second part of the study involves, biological evaluation against wild type C-SA enzyme and characterization of the synthesized compounds by Nuclear Magnetic Resonances (NMR). All the synthesized novel compounds were evaluated against wild type C-SA enzyme for their ability to inhibit 50% of the enzyme’s activity (IC50). Some of the compounds reported herein showed promising activity by inhibiting the enzyme activity at concentrations of less than 0.6 nM. 2D NMR investigations employing a new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy (ROESY / NOESY) technique enabled the attainment of vital information about the 3D structure of these small linear peptides and peptoids in solution. The activity could be related to conformations induced by the PCU moiety on the coupled peptide side chain. Further quantum mechanics/molecular mechanics/molecular dynamics (QM/MM/MD) simulations were carried out to confirm the observed NMR experimental results. Docking studies were performed for the synthesized compounds. Binding energies obtained from the docking calculations were then used to further validate the experimental IC50 results. These experimental and theoretical methods provided valuable insight into the interaction mode of these cage peptide and peptoids inhibitors with the enzyme. / Thesis (Ph.D.)-Unversity of KwaZulu-Natal, Westville, 2012.

Through the serendipitous discovery of a palladium catalyzed conversion of ethylthiol esters to their corresponding aldehydes, the pyrrolo (1,4) benzodiazepine systems found in (+)-anthramycin 1a* and (+)-neothramycins A 2a and B 2b have been constructed from the diethylthiol esters 3 and 4 respectively. A key intermediate 5 for the total synthesis of (+)-anthramycin and a facile route to (+)-neothramycins A and B are thus provided. ftn*Please refer to dissertation for diagrams.

The first total synthesis of ($-$)-hapalindole G, a member of novel chlorine- and isonitrile-containing hapalindoles from the cultured cyanophyte Hapalosiphon fontinalis, is accomplished. Our 21-step synthesis of ($-$)-hapalindole G from ($-$)-carveol features a stereospecific introduction of chlorine next to a quaternary center via cleavage of the cyclopropane intermediate and facile elaboration of the indole moiety through a conjugate addition of lithium methyl methylthiomethyl sulfoxide to an enone followed by hydrolysis of the resultant adduct. The absolute configuration of ($-$)-hapalindole G has therefore been confirmed on the basis of the specific rotation of our synthetic sample. Also described herein is a novel tin-mediated radical indole synthesis by using o-isocyanostyrene derivatives as starting materials via 2-tri-n-butylstannyl-3-substituted indoles as intermediates. The 2-tri-n-butylstannyl-indoles were also subjected to the one-pot Stille coupling reaction and iodination. The iodoindoles were capable of further manipulation. Our efficient synthesis paves the way for a facile construction of a variety of 3- or 2,3-substituted indoles from readily accessible isonitriles.

An advanced intermediate 2 for the synthesis of antitumor antibiotic ($\pm$)-Fredericamycin $A$, 1, has been prepared. The synthetic route features a novel palladium(0)-mediated intramolecular spiroarylation of 3. This methodology allows access to the unusual spirocyclic ring skeleton characteristic of Fredericamycin $A$ from more readily accessible precursors, isoquinoline 4 and naphthalide 5. The syntheses of 4 and 5 are discussed. Preliminary model studies established an efficient pathway to structures related to 3. These initial studies also disclosed a means by which to generate spirocyclic ring systems of the type found in Fredericamycin $A$. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)