Conformationally restricted analogs of deoxynegamycin
Conformationally restricted analogs of deoxynegamycin
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DOI：
10.1016/j.bmcl.2004.04.036
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发表时间：
2004-06-21
影响因子：
2.7
通讯作者：
Patel, DV
中科院分区：
文献类型：
--
作者：
Raju, B;Anandan, S;Patel, DV
脱氧尼加霉素（1b）是一种蛋白质合成抑制剂，对革兰氏阴性（GN）细菌有活性。合成了一系列构象受限的类似物以探究其生物活性构象。实际上，在蛋白质合成测定中发现一些受限类似物与脱氧尼加霉素效果相当或更好（1b，半数抑制浓度IC₅₀ = 8.2 μM；44，IC₅₀ = 6.6 μM；35e(2)，IC₅₀ = 1 μM）。然而，脱氧尼加霉素具有最佳的体外全细胞抗菌活性（大肠杆菌，最低抑菌浓度MIC为4 - 16 μg/mL；肺炎克雷伯菌，MIC = 8 μg/mL），这表明其他因素如渗透作用可能也对整体全细胞活性有贡献。一个新的发现是脱氧尼加霉素在大肠杆菌小鼠败血症模型中有效（半数有效剂量ED₅₀ = 4.8 mg/kg），为这类分子良好的体内特性提供了进一步的证据。（C）2004年由爱思唯尔有限公司出版
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC50 = 8.2 muM; 44, IC50 = 6.6 muM; 35e(2), IC50 = 1 muM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC 4-16 mug/mL; Klebsiella pneumoniae, MIC = 8 mug/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED50 = 4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules. (C) 2004 Published by Elsevier Ltd.