Endangered plant species for potential drug leads and anticancer prototypes for treatment of breast and pancreatic cancers

This research features the isolation, structural elucidation, and synthesis of natural products from rare and endangered plant species and marine sponges.;Part I elaborates the identification of bioactive phytochemicals from several rare or endangered plant species including Lindera melissifolia, Rhododendron brachycarpum, and Diplostephium rhododendroides. Worldwide at least 13% of known flora are endangered or threatened and the United States Department of Agriculture (USDA) reported that there are over 780 endangered or threatened plant species in the US and its territories. The essential oil and solvent extracts from L. melissifolia (pondberry) drupes were gathered, purified, and analyzed by various spectrometric techniques. The essential oil exhibited a significant dose dependent repellent activity against ticks reported to be vectors of significant pathogenic human diseases such Lyme disease. A Korean endangered plant R. brachycarpum was also rigorously investigated for bioactive molecules. R. brachycarpum is a broad-leaved shrub native to northern parts of Korea and Japan. The high mobility group box 1 protein (HMGB1) could be a specific target for the discovery of effective agents to alleviate severe sepsis. The first bicyclic megastigmane glucoside rhododendroside A was isolated from the leaves of R. brachycarpum. Gauge-invariant atomic orbital (GIAO) NMR chemical shift calculations were implemented for elucidation of stereochemical details of rhododendroside A with accuracy improved by application of DP4 analysis. One of the rare South American plant species D. rhododendroides Hieron. afforded diplostephiosides A and B. These secondary metabolites exerted inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) that has captured widespread attention in development of agents for the treatment of metabolic disorders. Comprehensive induced-fit docking simulations were implemented with diplostephiosides A and B and they demonstrated excellent docking scores with the allosteric binding sites.;Part II delineates not only the characterization of the stereostructure of BRCA1-IRIS (IRIS) inhibitory peptide exhibiting potent in vivo cytotoxic activity on triple-negative breast cancer (TNBC) but also the partial synthesis of a sponge-derived cytotoxic drug prototype for treatment of pancreatic cancer. Breast cancer is the second most diagnosed cancer in American women. Based on a recent study corroborating that the oncogenicity of IRIS resides with the intron 11 peptide domain, an IRIS-inhibitory peptide (IRIS-IP), composed of the oncogenic intron sequence attached to a nuclear penetrating signal, was designed and its 3D structure was elucidated utilizing high-field NMR spectroscopic and computational tools. Pancreatic cancer has also been recognized as a major cause of death in the West. In 2015, an estimated 48,960 people in the US will be diagnosed with pancreatic cancer and about 20,710 will die from the serious disease. Discorhabdin X, isolated from Latrunculia species collected in the deep waters off the Aleutian Islands, possesses intriguing ring systems and exhibited selective cytotoxic activity on pancreatic cancer. A partial structural moiety of this antineoplastic molecule is being synthesized to further evaluate in vivo cytotoxic activity for the development of a practical drug prototype targeting the treatment of pancreatic cancer and its related fatalities.