SYNTHESIS OF THE DIDEMNIN DEPSIPEPTIDE ANTIBIOTICS

这项建议涉及研究开发全合成的方法。 在白粉菌素多肽中，从白粉菌中分离出的一组抗生素 加勒比海的一种被囊动物。抗生素之所以引起人们的兴趣，是因为它们 在低剂量水平下具有显著的抗病毒和抗肿瘤活性。这个 抗生素的特征是一个由23个成员组成的环 L-苏氨酸，一种新的氨基酸，4-羟基-3-酮-2， 构型未知的5-二甲基己酸、L-亮氨酸、L-脯氨酸和 N，O-二甲基-1-酪氨酸。各种氨基酸或多肽单位附着在 L-苏氨酸的α-氨基组成了白粉菌素A、B和C。 该项目将专注于准备，通过负担得起的方法 新型4-羟基-3-酮-2，5-二甲基己酸的立体化学控制 抗生素中常见的酸。该单位的成立，以及 将新的氨基酸epistatine，转化为相应的线型脱脂肽 将对抗生素的环状部分进行研究。环化 提供二异氰酸酯的环状成分的线状前体将 被调查。环状脱脂肽将在 L-苏氨酸的氨基功能，在解除保护后将允许 在这个位置上的氨基酸或二肽单元的结合以提供 二氢杨梅素A、B和C或其类似物。合成的敌敌畏将会 进行抗肿瘤和抗病毒活性评估。

This proposal involves studies to develop methods for the total synthesis of the didemnin depsipeptides, a group of antibiotics isolated from Caribbean tunicates. The antibiotics are of interest due to their significant antiviral and antitumor activities at low dosage levels. The antibiotics are characterized by a 23-membered ring composed of L-threonine, the novel amino acid epistatine, a 4-hydroxy-3-keto-2, 5-dimethylhexanoic acid of unknown configuration, L-leucine, L-proline, and N,O-dimethyl-1-tyrosine. Various amino acid or peptide units attached to the alpha-amino group of L-threonine constitute the didemnins A, B, and C. The project will focus on the preparation, by methods that afford stereochemical control, of the novel 4-hydroxy-3-keto-2,5-dimethylhexanoic acid common to the antibiotics. The incorporation of this unit, along with the novel amino acid epistatine, into a linear depsipeptide corresponding to the cyclic portion of the antibiotic will be studied. Cyclization of the linear precursor to provide the cyclic component of the didemnins will be investigated. The cyclic depsipeptide will contain protection at the amino function of L-threonine, which upon deprotection will allow incorpoation of amino acid or dipeptide units at this position to furnish didemnins A, B, and C or analogues thereof. The synthetic didemnins will be evaluated for antitumor and antiviral activities.