Sch 217048: A novel cyclodepsipeptide with neurokinin antagonist activity
Sch 217048: A novel cyclodepsipeptide with neurokinin antagonist activity
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DOI：
10.1021/jo981467j
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发表时间：
1998-12-11
影响因子：
3.6
通讯作者：
Patel, M
中科院分区：
文献类型：
--
作者：
Hegde, VR;Puar, MS;Patel, M
神经激肽 (NK) 是一个由 9-11 个氨基酸组成的肽家族，可引发多种炎症反应。 1, 2 最充分表征的神经激肽，即 P 物质、NKA 和 NKB，参与多种反应，包括疼痛传递、神经源性炎症、支气管收缩和血管舒张。这些肽主要通过七个跨膜结构域 G 蛋白偶联受体发挥作用，这些受体已被克隆，称为 NK1、NK2 和 NK3，分别对 P 物质、NKA 和 NKB 具有选择性亲和力。 3 已鉴定出多种神经激肽拮抗剂，这些拮抗剂有助于阐明神经激肽在包括哮喘在内的多种疾病中的病理生理作用。 4 在寻找新型神经激肽受体抑制剂的过程中，我们从一种未鉴定的真菌发酵液中分离出了一种具有选择性 NK2 拮抗剂型活性的环缩肽 (Sch 217048, 1)。 5 在pH～6.5下用EtOAc萃取发酵液。 6 使用凝胶过滤 (Sephadex LH-20/MeOH) 和反相制备型 HPLC（Waters Deltapak C-18, 3.0× 30 cm, ACN: 0.05% TFA (35: 65)）通过 NK2 测定引导的分级分离实现 1 的纯化。纯化合物为白色，最终紫外吸收，熔点为192-194℃。在本文中，我们报道了1的结构解析。通过HRFABMS确定1的分子式为C57H88N10O14 [(M+ H)+ at m/z 1137.6560，计算值； 1137.6591，测量]以及 1H 和 13C NMR 谱（表 1）表明是一种肽。 1 为茚三酮阴性，表明 N 末端被封闭或为环肽。 1H、13C、APT 和 DEPT NMR 谱中包含的数据表明 11 个甲基（6 个双峰、2 个三峰、3 个 NMe 单峰）、15 个亚甲基（12 个 CH2、3 个 NCH2）、13 个次甲基（8 个 CHN、1 个 CHO、4 个 CH-CH3）、5 个C57H81 具有芳香族碳 (dCH) 和 13 个季碳 (12 CON (O)、1 dC)，加上由 4 个 NH、1 个酰胺 NH2 和 1 个羧酸质子组成的 7 个杂原子质子。由分子式计算出的19个不饱和度分为：12个羰基、3个三取代双键、1个脯氨酸、1个哌啶酸(pip)、1个苯环，最后由于环肽而有1个。对 COSY、HOHAHA、HETCOR、HMBC 和 HMQC-TOCSY NMR 数据的广泛分析揭示了氨基酸的自旋系统； Phe、Pro、Gly、MeVal、MeGln、Ile、Pip（哌可酸）、Val 和 MeGlu。另外，含有羟基次甲基官能团的酸
Neurokinins (NK), a family of 9-11 amino acid peptides, trigger a variety of inflammatory responses. 1, 2 The most well characterized neurokinins, namely substance P, NKA, and NKB, are involved in a variety of responses including pain transmission, neurogenic inflammation, bronchoconstriction, and vasodilation. The peptides act principally through seven transmembrane domain G protein-coupled receptors that have been cloned and are termed NK1, NK2, and NK3 and have selective affinity for substance P, NKA, and NKB, respectively. 3 A number of neurokinin antagonists have been identified, and these have been useful in clarifying the pathophysiologic roles of neurokinins in a variety of diseases including asthma. 4 During our search for novel neurokinin receptor inhibitors, we have isolated a cyclodepsipeptide (Sch 217048, 1) from an unidentified fungal fermentation broth with selective NK2 antagonist-type activity. 5 The fermentation was extracted with EtOAc at pH∼ 6.5. 6 Purification of 1 was achieved by NK2 assay-guided fractionation using gel filtration (Sephadex LH-20/MeOH) and reverse phase preparative HPLC (Waters Deltapak C-18, 3.0× 30 cm, ACN: 0.05% TFA (35: 65)). Pure compound was white with end UV absorption and a mp of 192-194 C. In this paper, we report the structure elucidation of 1. The molecular formula for 1 was determined to be C57H88N10O14 by HRFABMS [(M+ H)+ at m/z 1137.6560, calcd; 1137.6591, measured], and 1H and 13C NMR spectra (Table 1) were indicative of a peptide. 1 was ninhydrin-negative, indicating a blocked N-terminus or a cyclic peptide.Data contained in the 1H, 13C, APT, and DEPT NMR spectra indicated 11 methyls (6 doublets, 2 triplets, 3 NMe singlets), 15 methylenes (12 CH2, 3 NCH2), 13 methines (8 CHN, 1 CHO, 4 CH-CH3), 5 aromatic type carbons (dCH), and 13 quaternary carbons (12 CON (O), 1 dC) for C57H81 plus 7 heteroatom protons consisting of 4 NH, 1 amide NH2, and 1 carboxylic acid proton. The 19 degrees of unsaturation calculated from the molecular formula were divided as follows: 12 carbonyls, 3 trisubstituted double bonds, 1 proline, 1 pipecolic acid (pip), 1 benzene ring, and finally 1 due to cyclic peptide. Extensive analysis of COSY, HOHAHA, HETCOR, HMBC, and HMQC-TOCSY NMR data revealed spin systems for the amino acids; Phe, Pro, Gly, MeVal, MeGln, Ile, Pip (pipecolic acid), Val, and MeGlu. In addition an acid containing a hydroxymethine function