奈替米星4'-衍生物的合成、核糖体选择性及抗菌活性
Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4'-derivatives.
作者信息
Sonousi Amr, Shcherbakov Dimitri, Vasella Andrea, Böttger Erik C, Crich David
机构信息
Department of Chemistry , Wayne State University , 5101 Cass Avenue , Detroit , MI 48202 , USA . Email:
Institut für Medizinische Mikrobiologie , Universität Zürich , 28 Gloriastrasse , 8006 Zürich , Switzerland.
出版信息
Medchemcomm. 2019 Apr 25;10(6):946-950. doi: 10.1039/c9md00153k. eCollection 2019 Jun 1.
Halogenation of a suitably protected netilmicin derivative enables preparation of 4'-chloro-, bromo-, and iodo derivatives of netilmicin after deprotection. Suzuki coupling of a protected 4'-bromo derivative with phenylboronic acid or butyltrifluoroborate affords the corresponding 4'-phenyl and 4'-butyl derivatives of netilmicin. Sulfenylation of suitably protected netilmicin derivative with ethanesulfenyl chloride followed by deprotection affords 4'-ethylsulfanylnetilmicin. All netilmicin 4'-derivatives displayed reduced levels of inhibition for prokaryotic ribosomes and reduced antibacterial activity against typical Gram-positive and Gram-negative strains. None of the derivatives displayed enhanced target selectivity.
对适当保护的奈替米星衍生物进行卤化，能够在脱保护后制备奈替米星的4'-氯、溴和碘衍生物。将受保护的4'-溴衍生物与苯硼酸或丁基三氟硼酸盐进行铃木偶联反应，可得到奈替米星相应的4'-苯基和4'-丁基衍生物。用乙硫酰氯对适当保护的奈替米星衍生物进行亚磺酰化反应，然后脱保护，可得到4'-乙硫基奈替米星。所有奈替米星4'-衍生物对原核核糖体的抑制水平均降低，对典型革兰氏阳性和革兰氏阴性菌株的抗菌活性也降低。没有一种衍生物表现出增强的靶标选择性。
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