Synthesis and Evaluation of Anti-Tumor Flavanoids

描述（由申请人提供）：本研究的总体目标是开发和利用不对称催化合成抗前列腺癌（PCa）黄酮类化合物。前列腺癌是美国男性癌症死亡的第二大常见原因，死亡通常由转移引起。治疗PCa的新疗法将对美国的健康产生直接和有益的影响。 大豆中的主要成分染料木黄酮抑制前列腺癌细胞的细胞脱离和细胞侵袭以及转移的起始步骤。最近，我们发现2，3-二氢异黄酮具有抗侵袭活性。这使我们相信异黄烷酮可能是一类有效对抗PCa转移的化合物。本研究的长期目标是：1）开发和利用不对称催化合成对映体富集的异黄烷酮，保持抗侵袭活性，但缺乏生长抑制活性; 2）合成和评价黄烷酮天然产物苦参素异水飞蓟宾B。我们的中心假设是，光学活性的黄酮类化合物是用于治疗前列腺癌的不发达分子，并且获得这些化合物的立体选择性方法将对化疗的未来产生巨大影响。在建议的资助期内，我的研究的具体目标是： 具体目标1：开发新的催化不对称方法以获得抗转移的对映体富集的C3取代异黄烷酮。利用Scheldt和Bergan最近开发的染料木黄酮结合位点模型，我们将能够设计和合成更有效和选择性的异黄烷酮。 具体目标二：合成黄酮类天然产物苦参素和异水飞蓟宾B。两种黄烷酮 显示抗PCa活性，但没有报道这些分子的对映选择性合成。 为了发现我们的化合物的生物靶点并相应地对其进行修饰，我们 与雷蒙德·伯根博士（Raymond Bergan）建立了合作关系，他是实验治疗学主任， Robert H.西北大学Feinberg医学院Lurie癌症中心。他领导了一个实验室研究项目，重点是PCa细胞运动的药理学操作。他将评估我们的化合物的抗转移功效，我们将使用他的测试结果来合成更具选择性和有效性的异黄酮类化合物并优化药代动力学特性。

DESCRIPTION (provided by applicant): The overall goal of this research is to develop and utilize asymmetric catalysis to synthesize anti-prostate cancer (PCa) flavanoids. PCa is the second most common cause of cancer death in US males, death with is usually caused by metastasis. New therapies to treat PCa will have a direct and beneficial impact on the health of the United States. Genistein, the principal isoflavone in soy, inhibits the initiating steps of cell detachment and cell invasion of prostate cancer cells as well as metastasis. Recently, we discovered that 2,3-dihydrogenistein maintains anti-invasive activity. This led us to believe that isoflavanones might be a class of compounds that is effective against PCa metastasis. The long-term goals of my research are to 1) develop and utilize asymmetric catalysis to synthesize enantioenriched isoflavanones that maintain anti-invasive activity but lack growth inhibitory activity and 2) synthesize and evaluate the flavanone natural products kurarinone isosilybin B. Our central hypothesis is that optically active flavanoids are underdeveloped molecules for the treatment of PCa and stereoselective methods to access these compounds will have a dramatic impact on the future of chemotherapy. The specific aims of my research during the proposed grant period are: Specific Aim 1: Develop new catalytic asymmetric methods to access antimetastatic enantioenriched C3 substituted isoflavanones. Utilizing the binding site model for genistein that was recently developed by Scheldt and Bergan, we will be able to design and synthesize more potent and selective isoflavanones. Specific Aim 2: Synthesize the flavanone natural products kurarinone and isosilybin B. Both flavanones display anti-PCa activity, yet no enantioselective syntheses of these molecules has been reported. In order to discover the biological targets of our compounds and accordingly modify them, we have established a collaboration with Dr. Raymond Bergan, the Director of Experimental Therapeutics for the Robert H. Lurie Cancer Center at the Feinberg School of Medicine at Northwestern University. He directs a laboratory based research program focusing on the pharmacologic manipulation of PCa cell motility. He will evaluate our compounds for their antimetastatic efficacy and we will use the findings of his testing to synthesize more selective and potent isoflavanoids and optimize pharmacokinetic properties.