Novel 12-membered non-antibiotic macrolides, EM900 series with anti-inflammatory and/or immunomodulatory activity; synthesis, structure?activity relationships and in vivo study-猫眼课题宝

具有抗炎和/或免疫调节活性的新型12元非抗生素大环内酯类EM900系列；

DOI：

10.1038/ja.2012.51

发表时间：

2012

期刊：

J. Antibiot.

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

Akihiro Sugawara;Akito Sueki;Tomoyasu Hirose;Hideaki Shima;Kiyoko S Akagawa;Satoshi?mura and Toshiaki Sunazuka

红霉素A(EMA)于1952年首次分离，是一种临床上常用的大环内酯类抗生素，对革兰氏阳性菌、革兰氏阴性球菌和支原体均有抗菌活性。20世纪80年代，Itoh等人发现EMA还具有胃肠运动刺激活性和抗炎和/或免疫调节活性。2和Kudoh等人，分别为3。基于这些发现，我们的研究小组一直在努力创造一种理想的衍生物，它具有特定的活性而不显示抗菌作用。我们已经发现了一种新的吗丁内酯衍生物(EM574，去N-甲基-N-异丙基-8，9-脱水红霉素A6，9-半缩醛)，它具有胃肠运动刺激活性，但没有抗菌活性。4-7由于其抗炎和/或免疫调节活性，EMA是治疗弥漫性泛细支气管炎、慢性鼻窦炎和囊性纤维化的有效药物。8此外，本课题组还报道了EMA在体外促进单核细胞向巨噬细胞分化，抑制T细胞增殖。9，10同样，14元大环内酯类化合物也具有抗炎和/或免疫调节活性，其表现为抑制炎症细胞因子的产生。11-13然而，EMA的具体行动模式尚未确定。具有抗炎和/或免疫调节活性但缺乏抗菌活性或胃肠动力刺激活性的大环内酯衍生物将非常有用，因为它们将有助于避免增加耐药性，并有助于将EMA治疗的任何不良反应降至最低。在之前的一篇论文中，14我们报道了我们开发的新型12元(8R，9S)-8，9-二氢-6，9-环氧基-8，9-脱水假红霉素A(EM900)及其类似物，具有促进单核细胞向巨噬细胞分化的能力，但缺乏抗菌活性。这为我们提供了一个新的、酸稳定的具有抗炎和/或免疫调节活性的12元大环内酯化学骨架，尽管详细的构效关系尚未阐明。从我们的初步研究中，我们了解到，无论是支链从C11位置上断开，还是支链部分在抗炎和/或免疫调节作用中都没有重要作用。因此，我们开始对地索胺部分上N，N-二甲氨基的类似物的合成感兴趣，这是受到我们对具有强大的模线样活性的红霉素衍生物，特别是吗丁内酯EM574的经验的启发。4一般说来，EMA的N，N-二甲氨基是产生抗菌活性的必需部分。相反，在基序样活性的情况下，N，N-二甲氨基的修饰显著增加了活性。4综上所述，我们设想N，N-二甲氨基的修饰可能作为增强抗炎和/或免疫调节活性的一种手段。本文报道了EM900的N，N-二甲氨基及其类似物(8R，9S)-de(30-N-甲基)-30-N-(对氯苯基)-8，9-二氢-6，9-环氧基-8，9-无氢假红霉素A(EM905)和(8R，9S)-De(30-N，N-二甲氨基)-30-吗啉-8，9-二氢-6，9-环氧基-8，9-无氢假红霉素A(EM914)的构效关系。这两种化合物EM905和EM914被发现对炎症性肠病(IBD)小鼠模型的治疗有效，即使在相当低的剂量下，与治疗性磺胺类药物柳氮磺胺吡啶相比也是如此。我们建议使用…

Erythromycin A (EMA), first isolated in 1952, 1 is a clinically useful macrolide antibiotic, active against both Gram-positive bacteria and Gram-negative cocci and mycoplasmas. In the 1980s, EMA was found to have two other promising biological properties, gastrointestinal motor-stimulating activity and anti-inflammatory and/or immunomodulatory activity by Itoh et al. 2 and Kudoh et al., 3 respectively. Based on these findings, our research group has been striving to create an ideal derivative, which exhibits a specific activity without showing antibacterial effect. We have already found a new motilide derivative (EM574, de-N-methyl-N-isopropyl-8, 9-anhydroerythromycin A 6, 9-hemiketal), which exhibited gastrointestinal motor-stimulating activity but showed no antibacterial activity. 4–7 As a result of its anti-inflammatory and/or immunomodulatory activity, EMA is an effective treatment for diffuse panbronchiolitis, 3 chronic sinusitis and cystic fibrosis. 8 Additionally, our group reported that EMA promotes monocyte to macrophage differentiation and inhibits proliferation of T cell in vitro. 9, 10 Likewise, 14-membered macrolides are also well known to possess anti-inflammatory and/or immunomodulatory activity, which are represented by inhibition of inflammatory cytokine production. 11–13 However, the detailed mode of action of EMA has not yet been determined. Macrolide derivatives with anti-inflammatory and/or immunomodulatory activity but lacking either antibacterial activity or gastrointestinal motorstimulating activity would be extremely useful, as they would help avoid promotion of drug resistance, as well as help to minimize any adverse effects of EMA treatment. In a previous paper, 14 we reported our development of the novel 12-membered (8R, 9S)-8, 9-dihydro-6, 9-epoxy-8, 9-anhydropseudoerythromycin A (EM900), and analogues thereof, possessing the ability to promote monocyte to macrophage differentiation but lacking antibacterial activity. This provided us with a novel, acid-stable 12-membered macrolide chemical skeleton with anti-inflammatory and/or immunomodulatory activity, although no detailed structure–activity relationships had been clarified. From our initial study, we learned that neither disconnection of the side chain bearing from the C11 position nor the cladinose moiety has an important role in the anti-inflammatory and/or immunomodulatory effects. Consequently, we became interested in synthesis of analogues of the N, N-dimethylamino group on desosamine moiety, inspired by our experience with erythromycin derivatives with a potent motiline-like activity, especially motilide EM574. 4 Generally, the N, N-dimethylamino group of EMA is an essential moiety for generating antibacterial activity. In contrast, in the case of motiline-like activity, modification of the N, N-dimethylamino group dramatically increases the activity. 4 Taken together, we envisioned that modification of the N, N-dimethylamino group might be possible as a means of increasing anti-inflammatory and/or immunomodulatory activity. In this communication, we report the elucidation of structure–activity relationships of the N, N-dimethylamino group of EM900, as well as those of the analogues,(8R, 9S)-de (30-N-methyl)-30-N-(pchlorobenzyl)-8, 9-dihydro-6, 9-epoxy-8, 9-anhydropseudoerythromycin A (EM905) and (8R, 9S)-de (30-N, N-dimethylamino)-30-morpholino-8, 9-dihydro-6, 9-epoxy-8, 9-anhydropseudoerythromycin A (EM914). The two compounds, EM905 and EM914, were found to be effective for treatment in a mouse model of inflammatory bowel disease (IBD), even at considerably low doses, compared with the therapeutic sulfa drug, sulfasalazine. We propose …

Novel 12-membered non-antibiotic macrolides, EM900 series with anti-inflammatory and/or immunomodulatory activity; synthesis, structure?activity relationships and in vivo study

具有抗炎和/或免疫调节活性的新型12元非抗生素大环内酯类EM900系列；

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