SYNTHESIS OF THE DIDEMNIN DEPSIPEPTIDE ANTIBIOTICS

该提案涉及研究开发全合成方法， didemnin缩酚酸肽，一组抗生素分离自 加勒比海被囊动物。 抗生素之所以令人感兴趣，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。 的 抗生素的特征在于由以下组成的23元环 L-苏氨酸，一种新的氨基酸epistatine，一种4-羟基-3-酮基-2， 5-未知构型的二甲基己酸、L-亮氨酸、L-脯氨酸和 N，O-二甲基-1-酪氨酸。 各种氨基酸或肽单元连接到 L-苏氨酸的α-氨基构成didemnin A、B和C。 该项目将侧重于准备工作， 新的4-羟基-3-酮基-2，5-二甲基己酸的立体化学控制 抗生素中常见的酸 这支部队的成立，沿着 将新氨基酸epistatine转化为相应的线性缩肽 将研究抗生素的环状部分。 环化 提供didemnins的环状组分的线性前体将 追究 环状缩酚肽将在其末端含有保护。 L-苏氨酸的氨基功能，其在脱保护后将允许 在该位置引入氨基酸或二肽单元， didemnins A、B和C或其类似物。 合成的didemnins将 评估抗肿瘤和抗病毒活性。

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.