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先导。 俄亥俄州立大学(OSU)核心2的作用是通过开发 这些药物中最有希望的是，加快它们在体内生物模型中的测试，并增加它们的 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， 对药物开发过程至关重要的两个学科。在此核心中生成的化合物和数据将是 由乔安娜·伯德特博士领导送往核心1，以协助体外研究和构效关系(SAR) 对铅的分析，作用机制的确定，以及体内研究。同样，化合物也将是 酌情与项目1、2和3分享。考虑到这一点，以下是核心2的目标： (1)合成足够数量的精选天然产物，以进行更广泛的生物学评价；(2) 探索构效关系(SAR)和优化极具前景的药理性质 通过对天然产物支架进行系统的改性，(3)支持结构分配 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) 建立灵敏、选择性、准确和精密的分析方法，在体外和体外定量先导化合物 体内生物基质，(5)表征给药中先导化合物的溶解性、稳定性和代谢特征 制剂和体外细胞和酶制剂，以支持最佳配方和衍生化，如 必要的，和(6)产生试点的血浆浓度-时间曲线，并确定蛋白质和血细胞结合 在小鼠体内早期评估进入中空纤维前的选定化合物的药代动力学性质 化验。具体目标6的研究将与生物统计小组(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).