TOTAL SYNTHESIS OF STREPTOLYDIGIN AND RELATED SUBSTANCES

这项研究提案概述了完成总目标的战略。 替兰霉素B和链霉菌素的合成 合成替兰霉素A的新方法 和链溶菌素是二烯酰基四酸家族的成员。 从不同菌株的链霉菌中分离的抗生素。 溶链菌素已被证明可以选择性地抑制末端 脱氧核苷酸转移酶(TDT)，一种大量存在的酶 在白血病淋巴母细胞中，但在正常白细胞中不存在。TDT被认为是 在这些癌细胞的细胞代谢中起着至关重要的作用。它 可能是链球菌素/替兰霉素或这些天然药物类似物 这些产品将被证明对治疗各种白血病有效。 该提案还包含关于制定 螺酮和哌酮类化合物的合成方法学。使用这个 方法学，我们建议合成螺酮类化合物。 驱虫药阿维菌素B1B和B2B，以及糖苷酶抑制剂 1-脱氧诺吉霉素、N-甲基-1-脱氧诺吉霉素和1-脱氧甘露糖霉素。 糖苷酶抑制剂用于表征所涉及的溶酶体酶 在糖蛋白的生物合成和加工中，并测定 溶酶体病与溶酶体代谢正常的关系 各州。人类溶酶体储存疾病是已知的每一种 被这些物质抑制的糖苷酶及其活性的研究 抑制活性将有助于理解异常代谢 与这些人类疾病有关。

This research proposal outlines strategies for the completion of the total synthesis of tirandamycin B and streptolydigin which is patterned after the approach developed for the synthesis of tirandamycin A. The tirandamycins and streptolydigin are members of the dienoyl tetramic acid family of antibiotics isolated from various strains of Streptomyces. Streptolydigin has been shown to selectively inhibit terminal deoxynucleotidyl transferase (TDT), an enzyme present in large quantities in leukemic lymphoblasts, but not in normal leucocytes. TDT is believed to play a crucial role in the cellular metabolism of these cancer cells. It is possible that streptolydigin/tirandamycin or an analog of these natural products will prove effective in the treatment of various leukemias. The proposal also contains sections concerning the development of methodology for the synthesis of spiroketals and piperidones. Using this methodology, we propose to synthesize the spiroketal moieties of the anthelmintic compounds avermectin B1b and B2b, and glycosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin, and 1-deoxymannojirimycin. Glycosidase inhibitors are used to characterize lysosomal enzymes involved in the biosynthesis and processing of glycoproteins and to determine the relationship between normal lysomal metabolism and lysosomal disease states. A human lysosomal storage disease is known for each of the glycosidases which are inhibited by these substances and study of their inhibitory activity will aid in understanding the aberrant metabolism associated with these human disorders.