Wakiyama Yoshinari, Kumura Ko, Umemura Eijiro, Masaki Satomi, Ueda Kazutaka, Watanabe Takashi, Yamamoto Mikio, Hirai Yoko, Ajito Keiichi
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
J Antibiot (Tokyo). 2016 Jun;69(6):428-39. doi: 10.1038/ja.2015.125. Epub 2015 Dec 16.
Lincomycin derivatives, which possess a hetero ring at the C-7 position via sulfur atom, were synthesized by three types of reactions: (1) Mitsunobu reaction of 2,3,4-tris-O-(trimethylsiliyl)lincomycin (1) with the corresponding thiol, (2) SN2 reaction of 7-O-methanesulfonyl-2,3,4-tris-O-(trimethylsiliyl)lincomycin (2) with the corresponding thiol and (3) Pd-catalyzed cross-coupling reaction of 7-deoxy-7-epi-7-mercaptolincomycin (35) with the corresponding aryl halides. As a result, compound 28 had potent antibacterial activities against major pathogens, which caused respiratory infections, even compared with clindamycin. On the other hand, compound 38 showed most potent activities against a variety of Streptococcus pneumoniae with erm gene.
林可霉素衍生物通过三种类型的反应合成，这些衍生物在C-7位通过硫原子连接一个杂环：（1）2,3,4-三-O-（三甲基硅基）林可霉素（1）与相应硫醇的 Mitsunobu 反应；（2）7-O-甲磺酰基-2,3,4-三-O-（三甲基硅基）林可霉素（2）与相应硫醇的SN2反应；（3）7-脱氧-7-表-7-巯基林可霉素（35）与相应芳基卤化物的钯催化交叉偶联反应。结果，化合物28对引起呼吸道感染的主要病原体具有强效抗菌活性，甚至与克林霉素相比也是如此。另一方面，化合物38对多种带有erm基因的肺炎链球菌显示出最强的活性。
