| Part I. Rational Design and Synthesis of Artemisinin-Derived Antimalarials Malaria currently plagues half of the world's population, resulting in roughly one to three million deaths, annually. Despite being an ancient disease, we have yet to eradicate the parasites responsible. These Plasmodium parasites are able to rapidly mutate and have developed resistance to the commonly used antimalarial drugs. Therefore, the design, syntheses, and biological testing of new antimalarials are necessary. The natural product, artemisinin, is one of the most potent antimalarials to date and is used in many current antimalarial chemotherapies around the world. However the approved artemisinin compounds behave poorly in the body. Therefore, several diverse libraries of artemisinin-derived compounds were designed to improve upon these properties. When combined with a co-drug, some compounds were highly efficacious against P. berghei-infected mice. Several of these promising artemisinin derivatives were, also, highly potent against P. falciparum-infected human erythrocytes in vitro..;Part 2. Highly Stereocontrolled and Regiocontrolled Syntheses of Polyoxygenated [2.2.2]Oxabicyclic Synthons Highly oxygenated cyclohexanes (known as cyclitols or carba-sugars) were synthesized regiospecifically and stereoselectively via a key inverse electron demand Diels-Alder cycloaddition of electron poor 2-pyrones with the electron rich tert-butyldimethylsilyl vinyl ether. The resulting [2.2.2]oxabicyclic lactones proved to be versatile synthons; functionalization was achieved with very high stereocontrol. Using this method, up to five stereocenters were formed from commercially available or easily prepared planar starting materials.;Part 3. Synthesis and Biological Activity of Potential Seed Germinating Michael Acceptors Twenty years ago, ecologists noticed smoke's ability to enhance plant growth due to the rapid rebirth of forests after fires. A class of butenolides, called karrikins, was identified and was determined to be the cause of this enhancement in seed germination. Their mechanism of action is thought to be centered around their Michael accepting abilities, but unfortunately, their syntheses are low yielding. Therefore, more easily prepared Michael accepting pyrones and pyranylidenes were designed, synthesized, and tested for their promotion of seed germination.;Part 4. Synthesis and Antiproliferative Activity of Novel Vitamin D3 Derivatives Vitamin D3 is a secosteroid prohormone that is obtained through either the diet or through irradiation of skin by the sun. Inside the body, it is anabolized to the active metabolite, calcitriol. Calcitriol is most commonly known for its impact on calcium and phosphorus homeostasis; however, vitamin D receptors have been found in over thirty other types of tissue, including several cancer cells lines. Therefore, vitamin D3 derivatives have been designed to improve upon the drug's antiproliferative nature, whilst diminishing the undesirable role it plays on calcium mobilization. Two novel vitamin D3 derivatives were designed and synthesized, one of which was found to be highly antiproliferative and low-calcemic. |
