SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

• 批准号: 3276481
• 负责人: Amos B Smith
• 金额: $ 23.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-04-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276481
• 关键词: Streptomyces; anthelmintics; antibody dependent killer cell; antiinfective agents; antileukemic agent; antineoplastic antibiotics; conformation; cyclosporines; drug design /synthesis /production; drug screening /evaluation; immunochemistry; immunosuppressive; lactones; macrolide antibiotics

The principal goal of this research program (GM-29028) has been and will continue to be, the development of efficient, enantiospecific synthetic strategies for the construction of architecturally novel macrolides possessing significant pharmacological properties. During the first grant period (01-03), we achieved the first total synthesis of milbemycin beta 3, the simplest member of the avermectin-milbemycin family of anthelmintic macrolide antibiotics. Currently we have underway two viable strategies for the southern hemisphere of the milbemycin-avermectin targets. Prospects for the completion of milbemyucin alpha 1 are excellent. As a new target for the 08-11 years, we have selected the immunosuppressant FK506 (12), a novel 23-membered macrolide recently isolated by the Fujisawa Pharmaceutical Co., Ltd. from Streptomyces tsukubaensis no. 9993. Over the past ten years, the introduction of powerful immunosuppressants has led to tremendous advances in the area of human organ transplantation. Post-operative graft rejection however continues to be the foremost problem currently faced by transplant surgeons. The discovery and development of new immunosuppressant drugs is therefore of utmost importance to transplant surgery. FK506 appears to be an exceptionally promising candidate: in vivo, it inhibits T-lymphocytes, MLR, generation of killer T cells and appearance of IL-2 receptors, and thereby hypersensitivity reactions, at 30-100 times lower concentration than cyclosporin A, the most effective immunosuppressant available to date. FK506 is therefore an important target for total synthesis, not only for its intrinsic synthetic challenge, but also due to its extrinsic worth to the field of medicine.

该研究计划的主要目标（GM-29028）是 并将继续是高效的发展， 构造建设的对映体综合策略 建筑新颖的大花环具有重要意义 药理特性。 在第一个赠款期（01-03）， 我们实现了米尔贝霉素β3的第一个总合成， Avermectin-milbemycin家族的最简单成员 驱虫剂大环内酯类抗生素。 目前我们正在进行 南半球的两种可行策略 Milbemycin-Avermectin靶标。 完成的前景 Milbemyucin alpha 1非常出色。 作为08-11年的新目标，我们选择了 免疫抑制剂FK506（12），一种新颖的23元大花环 最近由富士岛制药有限公司孤立 Tsukubaensis链霉菌9993。在过去的十年中， 引入强大的免疫抑制剂已导致 人体器官移植领域的巨大进步。 但是，术后移植的拒绝仍然是 移植外科医生目前面临的最首要问题。 这 新的免疫抑制药物的发现和开发是 因此，对于移植手术至关重要。 FK506 似乎是一个异常有前途的候选人：在体内， 抑制T淋巴细胞，MLR，杀手T细胞的产生和 IL-2受体的出现，从而超敏反应 反应，浓度比环孢菌素低30-100倍 a，迄今为止可用的最有效的免疫抑制剂。 因此，FK506是总合成的重要目标，而不是 仅是因为其内在的合成挑战，也是由于其 外部价值对医学领域。