고체상 합성법에 의해 합성된 N-(3-hydroxysulfonyl)-L-homoserine Lactone 유사체들의 Vibrio harveyi 쿼럼 센싱에 대한 저해 효과
Solid Phase Synthesis of N-(3-hydroxysulfonyl)-L-homoserine Lactone Derivatives and their Inhibitory Effects on Quorum Sensing Regulation in Vibrio harveyi
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The inhibitors against Vibrio harveyi quorum sensing (QS) signaling were developed by modifying the molecular structure of the major signal, N-3-hydroxybutanoyl-L-homoserine lactone (3-OHC4- HSL). A series of structural derivatives, N-(3-hydroxysulfonyl)-L-homoserine lactones (HSHLs) were synthesized by the solid-phase organic synthesis method. The in vivo QS inhibition by these compounds was measured by a bioassay system using the V. harveyi bioluminescence, and all showed significant inhibitory effects. To analyze the interaction between these compounds and LuxN, a 3-OH-C4-HSL receptor protein of V. harveyi, we tentatively determined the putative signal binding domain of LuxN based on the sequence homology with other acyl-HSL binding proteins, and predicted the partial 3-D structure of the putative signal binding domain of LuxN by using ORCHESTRA program, and further estimated the binding poses and energies (docking scores) of 3-OH-C4-HSL and HSHLs within the domain. In comparison of the result from this modeling study with that of in vivo bioassay, we suggest that the in silico interpretation of the interaction between ligands and their receptor proteins can be a valuable way to develop better competitive inhibitors, especially in the case that the structural information of the protein is limited.
Abstract
The inhibitors against Vibrio harveyi quorum sensing (QS) signaling were developed by modifying the molecular structure of the major signal, N-3-hydroxybutanoyl-L-homoserine lactone (3-OHC4- HSL). A series of structural derivatives, N-(3-hydroxysulfonyl)-L-homoserine lactones (HSHLs) were synthesized by the solid-phase organic synthesis method. The in vivo QS inhibition by these compounds was measured by a bioassay system using the V. harveyi bioluminescence, and all showed significant inhibitory effects. To analyze the interaction between these compounds and LuxN, a 3-OH-C4-HSL receptor protein of V. harveyi, we tentatively determined the putative signal binding domain of LuxN based on the sequence homology with other acyl-HSL binding proteins, and predicted the partial 3-D structure of the putative signal binding domain of LuxN by using ORCHESTRA program, and further estimated the binding poses and energies (docking scores) of 3-OH-C4-HSL and HSHLs within the domain. In comparison of the result from this modeling study with that of in vivo bioassay, we suggest that the in silico interpretation of the interaction between ligands and their receptor proteins can be a valuable way to develop better competitive inhibitors, especially in the case that the structural information of the protein is limited.
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- "The NMR-data for the compound 6a: IH NMR (CDC13, 400 MHz) δ=7.89 (s, 1H, NH), 4.79 (s, 1H, OH) 4.53 (ddd, J=5.96 hz,1H, CH-Lac), 4.46 (ddd, J=5.96 hz, 1H, CH-Lac), 3.88 (m, 2 H, CH2), 3.47-3.44 (m, 1 H, CH-Lac), 2.90 (d, J=6.96 hz, 2H, CH2), 2.70 (d, J=6.12hz, 2H, CH2), 2.52-2.49 (m, 1H, CH-Lac), 2.10-2.08 (m, 1H, CH-Lac), 2.0 (s, 1H, NH), 1.65 (m. 2H, CH2), 1.48-1.39 (m. 8H, CH2); HRMS (CI) calcd for C13H24N2O5S (M+ + 1) 320.4100, found 320.4101 (Abbreviations: DIEA; diisopropyl ethylamine, HOBt; 1-hydroxybenzotriazole, BOP; benzotriazol-1-yl-oxytris( dimethylamino)phosphonium hexafluorophosphate, NMP; N-methyl-2-pyrrolidone, THF; tetrahydrofuran, and DMF; dimethylformamide)", ~