Core 2: Medicinal Chemistry and Pharmacokinetics Core

该计划的主要目标是从植物和地衣中发现天然产物（项目1）， 蓝藻（项目2）和丝状真菌（项目3），最终将作为抗癌药物的线索。 核心2在俄亥俄州州立大学（OSU）的作用是通过发展支持这些努力， 这些药物中最有前途的一种，加速了它们在体内生物模型中的测试，并增加了它们的 成功的可能性。为了实现这一目标，核心2结合了药物化学和药代动力学研究， 这两个学科对药物开发过程至关重要。本核心中生成的化合物和数据将 由Joanna Burdette博士领导的核心1，以协助体外研究和构效关系（SAR） 分析先导物、确定作用机制和体内研究。类似地，化合物也将是 酌情与项目1、2和3共享。考虑到这一点，核心2的目标如下： (1)合成足够数量的精选天然产物，用于更广泛的生物学评价，（2） 探索构效关系（SAR）并优化极具前景的药物的药理学性质。 通过系统修饰天然产物支架，（3）支持天然产物的结构分配， 必要时，通过化学合成和/或半合成衍生化分离的天然产物，（4） 开发灵敏、选择性、准确和精确的分析测定法，以定量体外和体内的先导化合物， 体内生物基质，（5）表征给药中先导化合物的溶解度、稳定性和代谢特征 制剂和体外细胞和酶制剂，以支持最佳制剂和衍生化， （6）产生试验性血浆浓度-时间曲线并测定蛋白质和血细胞结合 用于在进入中空纤维之前早期估计所选化合物药代动力学性质 测定。具体目标6中的研究将与生物统计组（核心A）协商进行。

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).