Synthesis and Evaluation of Anti-Tumor Flavanoids

描述(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)类黄酮。前列腺癌是美国男性癌症死亡的第二大常见原因，死亡通常是由转移引起的。治疗前列腺癌的新疗法将对美国的健康产生直接和有益的影响。 金雀异黄素是大豆中的主要异黄酮类化合物，可抑制前列腺癌细胞分离、侵袭和转移的起始步骤。最近，我们发现2，3-二氢异黄素具有抗侵袭活性。这使得我们相信异黄酮类化合物可能是一类有效抑制前列腺癌转移的化合物。我的长期研究目标是：1)开发和利用不对称催化合成保持抗侵袭活性但缺乏生长抑制活性的对映体富集型异黄酮类化合物；2)合成和评价黄烷酮类天然产物苦参素异水飞蓟宾B。我们的中心假设是，光学活性黄烷类化合物是治疗前列腺癌的不发达分子，立体选择性地获得这些化合物将对未来的化疗产生重大影响。在拟议的资助期内，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来获得抗肿瘤转移的富对映体C3取代异黄酮类化合物。利用Scheldt和Bergan最近开发的染料木素结合位点模型，我们将能够设计和合成更有效和更有选择性的异黄酮类化合物。 具体目标2：合成黄烷酮类天然产物苦参素和异水飞蓟宾B 显示了抗前列腺癌的活性，但这些分子的对映选择性合成尚未见报道。 为了发现我们化合物的生物靶标并相应地对它们进行修饰，我们已经 与实验治疗学主任雷蒙德·伯根博士建立了合作关系 西北大学范伯格医学院的罗伯特·H·卢里癌症中心。他领导着一个以实验室为基础的研究项目，重点是对前列腺癌细胞运动性的药物操纵。他将评估我们的化合物的抗肿瘤疗效，我们将利用他的测试结果来合成更有选择性和更有效的异黄烷类化合物，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.