| Vitamin D holds an essential role in human health by participating in important biological activities such as calcium and phosphorous homeostasis, cell differentiation, immunology, and regulation of gene transcription. The value of the hormone is recognized by chemists who design and synthesize analogs of 1alpha, 25-dihydroxyvitamin D3 for treatments of diseases such as osteoporosis, psoriasis, and a variety of cancers. An ongoing challenge in designing vitamin D3 analogs is finding an optimal balance between desired antiproliferative activity and low calciuria. Over a dozen sulfone analogs were designed and synthesized featuring small changes such as homologation and unsaturation of, and fluorine incorporation into the C,D-ring side chain. Several sulfones exhibited high antiproliferative activities and low calcemic levels.; During the synthesis of alpha,beta-unsaturated 1alpha, 25-dihydroxyvitamin D3 analogs, remote steric effects on conjugate addition reactions were evident during the critical Horner-Wadsworth-Emmons coupling. Examination of conjugated ethylenic sulfones, sulfoxides, ketones, and esters in Michael-type addition reactions reveals, for the first time, that the size of the heteroatom-attached alkyl group affects the rate of conjugate addition. Molecular modeling clearly shows that the alkyl groups in these Michael acceptors shield the beta-carbons in the following order: Et<i-Pr<t-Bu. Competition experiments establish the relative rates of Michael additions to be in the following order: Et>i-Pr>t-Bu.; In addition to the development of antiproliferative 1alpha, 25-dihydroxyvitamin D3 analogs, new orally active artemisinin-based dimers were also established. Antimalarial chemotherapy is faced with the dual challenge of widespread resistance of the infectious parasite, and the absence of resources to administer certain treatments in the economically underdeveloped countries where malaria is most prevalent. Artemisinin-based therapies are unique in that there is no known evidence of the widespread problem of parasite resistance. However, poor water and oil solubility challenge the development of efficacious artemisinin-based antimalarial treatments. Through the use of various linkers composed of functionalities such as esters, amides, urea-based ketals, and carbamates, artemisinin dimers were designed to optimize bioavailability. Several of the novel dimers increased the lives of the mice upon oral dosages of 3x30 mg/kg, 3x10 mg/kg, and even 1x30 mg/kg. |
