Mazzei T, Mini E, Novelli A, Periti P
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Antimicrob Chemother. 1993 Mar;31 Suppl C:1-9. doi: 10.1093/jac/31.suppl_c.1.
After the discovery of erythromycin and other natural compounds, including oleandomycin, spiramycin, josamycin and midecamycin, much research has been devoted to synthesizing derivatives or analogues with improved chemical, biological and pharmacokinetic properties. These new macrolides are semisynthetic molecules that differ from the original compounds in their substitution pattern of the lactone ring system. The chemical structure of macrolides is characterized by a large lactone ring containing from 12 to 16 atoms to which are attached, via glycosidic bonds, one or more sugars. The lactone ring is substituted by hydroxyl or alkyl groups, one ketone at C7 in 12-membered macrolides and at C9 in 14-membered macrolides, and one aldehyde group in 16-membered macrolides. The only compound with a 15-membered ring contains a tertiary amino group. Although the 12-membered macrolides have never become important in clinical practice, in recent years numerous new 14-membered macrolide derivatives of erythromycin A have shown improved pharmacokinetics due to chemical modifications of a hydroxyl group at C6, a proton at C8, or a ketone at C9. Derivatives, such as dirithromycin, roxithromycin, clarithromycin and flurithromycin, have all been synthesized with the aim of inhibiting their decomposition under acidic conditions to inactive anhydrohemiketal derivatives. A new 15-membered macrolide, azithromycin, with a methylated nitrogen inserted into the lactone ring shows good activity against Gram-negative bacteria. The efforts expended in chemical and biochemical modifications of 16-membered macrolides have been less successful, with only a few new molecules, such as rokitamycin and miocamycin, showing improved bioavailability and activity against some resistant micro-organisms.(ABSTRACT TRUNCATED AT 250 WORDS)
在发现红霉素及其他天然化合物（包括竹桃霉素、螺旋霉素、交沙霉素和麦迪霉素）之后，人们进行了大量研究以合成具有改善的化学、生物学和药代动力学性质的衍生物或类似物。这些新的大环内酯类药物是半合成分子，其内酯环系统的取代模式与原始化合物不同。大环内酯类药物的化学结构特征是含有12至16个原子的大内酯环，通过糖苷键连接一个或多个糖。内酯环被羟基或烷基取代，12元大环内酯类药物在C7位有一个酮基，14元大环内酯类药物在C9位有一个酮基，16元大环内酯类药物有一个醛基。唯一具有15元环的化合物含有一个叔氨基。尽管12元大环内酯类药物在临床实践中从未变得重要，但近年来，由于对红霉素A的C6位羟基、C8位质子或C9位酮基进行了化学修饰，许多新的14元大环内酯类衍生物显示出改善的药代动力学。诸如地红霉素、罗红霉素、克拉霉素和氟红霉素等衍生物的合成目的均是抑制其在酸性条件下分解为无活性的脱水半缩酮衍生物。一种新的15元大环内酯类药物阿奇霉素，其内酯环中插入了一个甲基化氮原子，对革兰氏阴性菌显示出良好活性。在16元大环内酯类药物的化学和生化修饰方面所做的努力不太成功，只有少数新分子（如罗他霉素和米卡霉素）显示出改善的生物利用度和对一些耐药微生物的活性。（摘要截短至250字）
