title: Natural Products from Australian Celastraceae Plants and Their Leucine Transport Inhibition in Prostate Cancer Cells
Creators: name: Wibowo, Mario
Publisher: name: Griffith University
Year: 2018
Subjects: subject: Celastraceae plants
subject: Leucine transport inhibition
subject: Cancer cells
subject: Alkaloid maytansine
subject: Transtuzumab emtansine

description: Natural products are the main source of approved medicines with more than half of the drugs on the market today being either natural products or natural product derivatives. Moreover, a significant number of these drugs are of plant origins. However, it has been estimated that of the &gt;422,000 plant species currently described, only 15% of this plant diversity have been phytochemically explored. Therefore, there still exists a huge potential in the plant kingdom for the discovery of new chemistry, some of which may result in the identification of lead compounds or drugs for the pharmaceutical industry. Several notable examples of plant-derived natural product drugs are the anticancer compounds vinblastine, vincristine, and paclitaxel, the antimalarial agents artemisinin and quinine, and the Alzheimer drugs galantamine and huperzine A. In regards to plant-derived lead compounds, two pertinent examples include camptothecin, which lead to the development of the anticancer agents, topotecan and irinotecan, and papaverine, which was the lead model for the antihypertension verapamil. The Celastraceae plant family is found worldwide, especially in tropical and subtropical regions; currently there are 88 genera and 1300 species belonging to this flowering plants family. Various molecules possessing numerous biological activities have been reported from Celastraceae. One noteworthy example of an interesting natural product and cancer lead compound from Celastraceae is the alkaloid maytansine, which was further developed into the antibody drug conjugate treatment, transtuzumab emtansine, and is currently used for breast cancer treatment. However, the characteristic secondary metabolites of Celastraceae are the dihydro-[beta]-agarofuran sesquiterpenoids, which have been reported in the literature as both chemotaxonomic markers and privileged structures. The L-type amino acid transporters (LATs) are responsible for the uptake of various amino acids (including leucine) into cells. Leucine is a regulator amino acid of the mTORC1 signalling pathway and one of the essential amino acids that is transported by LATs. Though LATs are expressed in both normal and cancer cells, the overexpression of LATs has been reported in various cancer cells, including those associated with prostate cancer. Thus, the inhibition of leucine uptake may be a novel drug target for cancer treatment. To date, very few natural product LATs inhibitors have been identified. Venulosides, which are all monoterpenoid glycosides, were the first and only natural products (reported by Quinn et al.) that had been reported to inhibit LATs prior to these PhD studies. Their recent discovery highlights the potential of natural products in the discovery of new LAT inhibitors. This knowledge coupled with an interest in the chemistry of the hitherto under-investigated Australian plant family, Celastraceae, motivated us to identify new small molecules from this particular biota and evaluate all compounds isolated or semi-synthesised for their ability to inhibit leucine uptake on the human prostate cancer cell line, LNCaP. The plants that were investigated during these PhD studies included Maytenus bilocularis, Denhamia pittosporoides, and Celastrus subspicata and Denhamia celastroides. [...]