Opening or Closing the Lock? When Reactivity Is the Key to Biological Activity

被引:38
作者
Al-Rifai, Nafisah [1 ]
Ruecker, Hannelore [1 ]
Amslinger, Sabine [1 ]
机构
[1] Univ Regensburg, Inst Organ Chem, D-93053 Regensburg, Germany
关键词
chalcones; electrophiles; inflammation proteins; reactivity tuning; thiols; MICHAEL ACCEPTORS; ACID-DERIVATIVES; CHALCONES; TRIFLUOROMETHYLATION; INHIBITORS; COVALENT;
D O I
10.1002/chem.201302117
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Thiol-mediated processes play a key role to induce or inhibit inflammation proteins. Tailoring the reactivity of electrophiles can enhance the selectivity to address only certain surface cysteines. Fourteen 2,3,4,4-tetramethoxychalcones with different -X substituents (X=H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) were synthesized, containing the potentially electrophilic ,-unsaturated carbonyl unit. The assessment of their reactivity as electrophiles in thia-Michael additions with cysteamine shows a change in the reactivity of more than six orders of magnitude. Moreover, a clear correlation between their reactivity and an influence on the inflammation proteins heme oxygenase-1 (HO-1) and the inducible NO synthase (iNOS) is demonstrated. As the biologically most active compound, the -CF3-chalcone is shown to inhibit the NO production in RAW264.7 mouse macrophages in the nanomolar range.
引用
收藏
页码:15384 / 15395
页数:12
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