Scientific Theme: Cancer
Abstract: The broad long-term objectives are to discover new potent and anti-cancer agents and to provide leads for pre-clinical trials. The specific aims are: 1) Synthesize new compounds that show these characteristics. 2) Explore their mechanisms of action. This project is consistent with the NIH mission of providing “fundamental knowledge about behavior of living systems,” and “application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” We aim to provide insight into the conundrums of the diseases that are cancer, and provide “fundamental knowledge” on the causes, preventions and chemotherapies of cancer, especially breast cancer, at the molecular and cellular levels. The research design and methods: during year one we will synthesize compounds and screen them in mouse mammalian cancer (4T1) and normal (MNuMG) cells, in luciferase assays for estrogenic activity and mitochondrial toxicity, and for DNA binding in gel electrophoresis and UV-monitored melting experiments. In year two we will continue this synthesis and screening program and begin to screen the most promising compounds from year one in MCF-7 and ZR-75-1 human breast cancer cells. The compounds we will synthesize and screen are: variations of molecules already shown in our labs or others’ to have some toxicity in one or more of these and other assays; compounds containing structural features that are common to many anti-cancer agents as revealed in a variety of in vitro screening protocols. Molecules discovered by 1) “Molinspiration Cheminformatics”© (online) and/or 2) “MUSE Invent”© (proprietary) will also be synthesized. The first takes input structures and calculates physical properties and scores fits to six protein receptors. The second begins with an input structure that includes a preserved core molecule with designated sites for chemical structure changes and a range of physical and chemical variations with which each structure must comply. A genetic algorithm then cycles through several “generations” of daughter structures to give a set of compliant molecules. These are then submitted to the docking program that scores best fits for the binding site of a designated protein. The proteins may be receptors or enzymes known or suspected to be involved in cancer biochemistry. An estrogen receptor is the receptor of first interest in our study due to its relevance in breast cancer and our preliminary observations of in vivo and in silico estrogenic activity for some of the compounds studied by us and others. Synthesis involve simple and efficient methods like those done in undergraduate organic chemistry teaching laboratories. “Muse” also has an algorithm that gives synthetic pathways for more novel molecules not attainable by these methods.
Human Health Relevance: Cancers in general and breast cancer in women in particular remain in the top causes of death and lifetimelimiting diseases worldwide. There are two sources of chemotherapeutic drugs; isolation of natural products from ever more exotic plant and animal sources or rational synthesis of small molecules in chemical laboratories. This project offers a contribution to the second method of attack. It combines computational selection and laboratory synthesis of compounds for toxicity screening to discover potential new anti-cancer agents.