Core 2: Medicinal Chemistry and Pharmacokinetics Core

点击翻译按钮获取中文摘要

The primary goal of this Program is the discovery of natural products from plants and lichens (Project 1), cyanobacteria (Project 2), and filamentous fungi (Project 3) that will ultimately serve as anticancer drug leads. The role of Core 2 at The Ohio State University (OSU) is to support these efforts through the development of the most promising of these agents, accelerating their testing in in vivo biological models and increasing their likelihood of success. To achieve this goal, Core 2 combines medicinal chemistry and pharmacokinetic studies, two disciplines critical to the drug development process. The compounds and data generated in this Core will be sent to Core 1, led by Dr. Joanna Burdette, to assist the in vitro studies and structure-activity relationship (SAR) analysis for leads, determination of mechanism of action, and in vivo studies. Similarly, compounds will also be shared with Projects 1, 2 and 3 where appropriate. With this in mind, the following are the objectives of Core 2: (1) Synthesize sufficient quantities of selected natural products for more extensive biological evaluation, (2) Explore structure-activity relationships (SAR) and optimize pharmacological properties of highly promising agents through systematic modification of the natural product scaffold, (3) Support the structural assignment of isolated natural products through chemical synthesis and/or semi-synthetic derivatization, as necessary, (4) Develop sensitive, selective, accurate and precise analytical assays to quantify lead compounds in in vitro and in vivo biological matrices, (5) Characterize solubility, stability and metabolic profiles of lead compounds in dosing formulations and in vitro cell and enzyme preparations to support optimal formulation and derivatization, as necessary, and (6) Produce pilot plasma concentration-time profiles and determine protein and blood cell binding in mice for early estimation of pharmacokinetic properties for select compounds prior to entry into hollow fiber assays. The studies in Specific Aim 6 will be conducted in consultation with the biostatistics group (Core A).