FUSARAOCHROMANONE: NEW ANALOGS AS POTENTIAL ANTICANCER AND ANTIANGIOGENIC AGENTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。血管生成是一个复杂的生物过程，控制着体内新血管的生长。正常情况下，成年人的血管生成是下调的，除了伤口愈合和月经周期。然而，异常血管生成与多种疾病有关，包括癌症、关节炎和视网膜病。2004年初，FDA批准Erbitux（Imclone）和Avastin（Genentech）用于治疗转移性结肠癌，抗血管生成剂在癌症治疗中的前景得以实现。这些分子都是单克隆抗体，它们与生长因子结合，使癌细胞能够向肿瘤和肿瘤周围生长。如果没有血液供应，肿瘤的直径不能超过2毫米。因此，抗血管生成癌症疗法已经延长和挽救了成千上万人的生命。特别有利的是开发能够以与上述蛋白质相同或更高的功效抑制血管生成的小分子。小分子药物具有明显的优势，因为它们通常可以口服给药，而且它们的成本远远低于蛋白质药物。该提案概述了癌症研究领域涉及药物发现的重要科学问题。它的目标是合成一种天然产物，Fusarochromanone，及其具有强效抗血管生成活性的新型酰胺类似物。还已知镰刀菌色满酮也表现出针对多种癌细胞系的活性。因此，这项研究最终可以提高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认识。

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.