FUSARAOCHROMANONE: NEW ANALOGS AS POTENTIAL ANTICANCER AND ANTIANGIOGENIC AGENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。血管生成是一个复杂的生物过程，它控制着体内新血管的生长。正常情况下，除了伤口愈合和月经周期外，成人的血管生成是下调的。然而，异常的血管生成与多种疾病有关，包括癌症、关节炎和视网膜病变。2004年初，随着FDA批准艾比特思(Imclone)和阿瓦斯丁(Genentech)用于治疗转移性结肠癌，抗血管生成药物在癌症治疗中的承诺实现了。这两种分子都是与生长因子结合的单抗，这些生长因子使癌细胞能够向肿瘤及其周围生长。如果没有血液供应，肿瘤的直径不可能超过2毫米。因此，抗血管生成癌症治疗已经延长并挽救了成千上万人的生命。开发能够抑制血管生成的小分子与上述蛋白质具有相同或更大的功效将是特别有利的。小分子药物具有明显的优势，因为它们通常可以口服，而且它们比蛋白质药物便宜得多。这项提案概述了癌症研究领域中涉及药物发现的一个重要科学问题。它的目标是合成一种天然产物Fusarochromanone及其具有强大抗血管生成活性的新型酰胺类似物。众所周知，Fusarochromanone还具有抗多种癌细胞的活性。因此，这项研究最终可以增强我们对血管生成和控制血管细胞和癌细胞生长的生长因子的知识。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Angiogenesis is a complex biological process that controls the growth of new blood vessels in the body. Normally, angiogenesis is down-regulated in adults, with the exception of wound healing and the menstrual cycle. Aberrant angiogenesis, however, has been implicated in a variety of diseases, including cancer, arthritis, and retinopathy. The promise of anti-angiogenic agents in cancer therapy came to fruition in early 2004 with FDA approval of both Erbitux (Imclone) and Avastin (Genentech) for the treatment of metastatic colon cancer. These molecules are both monoclonal antibodies that bind to growth factors that enable cancer cells to grow towards and around tumors. Without a blood supply, tumors are unable to grow beyond 2 mm in diameter. Thus anti-angiogenesis cancer therapy is already prolonging and saving thousands of peoples lives. It would be particularly advantageous to develop small molecules that can inhibit angiogenesis with the same or greater efficacy as the proteins described above. Small molecules offer distinct advantages in that they can usually be administered orally, and they are far less costly than protein drugs. This proposal outlines an important scientific problem involving drug discovery in the field of cancer research. It targets the synthesis of a natural product, Fusarochromanone, and its novel amide analogs with potent anti-angiogenic activity. Fusarochromanone is also known to exhibit activity against a variety of cancer cell lines as well. Thus, this research could ultimately enhance our knowledge of angiogenesis and the growth factors that control both the growth of blood vessel cells and cancer cells.