Chemistry

在该项目的这一组成部分上提供的药物化学和合成有机化学工作将提供天然产物合成以及与该项目的其他组成部分分离的化学预防剂的新型类似物的设计，合成和开发。对于以痕量分离的天然产物，其不允许在体外生物测定的期望组合中进行测试，需要提供100 mg至1 g范围内的量的实际合成。此外，可以预期的是，天然存在的化学预防测定的潜在治疗效用将受到常见因素的限制，包括缺乏足够的效力、化学不稳定性、允许配制的溶解度不足以及吸收、分布、代谢和排泄的限制以及毒性。可以预计，每 个别代理人将提出自己的一系列限制，这些限制将视需要逐案处理。例如，化学稳定性的缺乏将通过用具有增强的化学稳定性并保留所需生物活性的官能团取代不稳定部分来克服。缺乏内在活性（效力）将通过结构-活性关系的研究以及基于目标结构的合理设计，使用计算机图形分子建模方法来处理。溶解度不足将通过引入或消除允许盐形成的酸性和碱性官能团来克服。代谢不稳定性将通过用具有增强的代谢稳定性的生物活性部分替代代谢化基团来补救。毒性问题将通过前药方法来解决，其中原始化合物转化为无毒前体，其代谢回药物。 母体生物活性化合物。缺乏吸收可以通过操纵亲脂性或通过连接主动转运的载体部分来解决。如果药物不能以足够的浓度到达靶组织以产生所需的生物效应，则可以将其转化为具有更有利的分布特征的前药形式，或者可以将其转化为允许适当的生物效应的类似物。 用于通过不同途径给药的制剂。如果药物被消除得太快，它将被转化为一种类似物，这种类似物在肾小管中的重吸收和排泄机制方面具有改变的性质。这通常可以通过极性的改变来解决。可以预期，在任何特定时间进行研究的化学预防剂将随着项目其他部分的新兴分离、结构解析和生物学研究活动的进展而发生变化。我们的初步研究将集中在与白藜芦醇和白藜芦醇有关的多羟基化二苯乙烯类化合物，以及黄酮，生物碱和生物碱家族的化学预防剂。

The medicinal chemistry and synthetic organic chemistry efforts provided on this component of the program project will provide both natural product syntheses as well as the design, synthesis, and development of novel analogs of the chemopreventive agents isolated in connection with the other components of the project. For natural products that are isolated in trace amounts that do not permit testing in the desired battery of in vitro biological assays, practical syntheses are required that will provide quantities in the 100 mg to 1 g range. In addition, it can be expected that the potential therepeutic utilities of the naturally occurring chemopreventive assays will be limited by the usual factors including lack of sufficient potency, chemical instability, inadequate solubility to permit formulation, and limitations of absorption, distribution, metabolism, and excretion, and well as toxicity. It can be expected that each individual agent will present its own array of limitations, and these will be addressed on a case-by-case basis as the need arises. For example, lack of chemical stability will be overcome by substitution of the unstable moieties with functional groups that possess enhanced chemical stability with retention of the desired biological activity. Lack of intrinsic activity (potency) will be handled through the investiaton of structure-activity relationships as well as by rational design based on the target structure, using computer graphics molecular modeling approaches. Inadequate solubility will be overcome through incorporation or elimination of acidic and basic functionalities that permit salt formation. Metabolic instability will be remedied through in replacement of the metabilized groups with biologically active moieties having enhanced metabolic stabilities. Problems with toxicity will be solved through prodrug approaches in which the original compound is transformed into a non-toxic precursor that is metabolized back to the parent, biologically active compound in the target tissue. Lack of absorption can be solved either by manipulation of lipophilicity or by the attachment of carrier moieties that are actively transported. If the drug does not reach the target tissue in adequate concentrations to produce the desired biological effects, it can be converted to a prodrug form having more favorable distribution characteristics, or it can be converted to an analog that will allow appropriate formulation for administration by a different route. If the drug is eliminated too rapidly, it will be transforrmed into an analog that has altered properties with regard to reabsorption and excretion mechanisms in the renal tubules. This can often be addressed through a change in polarity. It can be anticipated that the chemopreventive agents that will be under investigation at any particular time will change as the emerging isolation, structure elucidation, and biological investigation activities progress in the other parts of the program project. Our intial investigations will focus on the polyhydroxylated stilbenes related to resveratrol and piceatannol, as well as the chemopreventive agents in the flavone, isoflavone, and alkaloid families.