Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies

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• 作者：Reena Chawla ; Victor Van Puyenbroeck ; Nicholas C. Pflug ; Alekhya Sama ; Rameez Ali ; Dominique Schols ; Kurt Vermeire ; Thomas W. Bell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2633-2647
• 全文大小：632K
• ISSN：1520-4804

文摘

Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogues bearing a benzyl tail group and nine bearing a cyclohexylmethyl tail have been designed and synthesized. The most potent new CD4 down-modulator (40 (CK147); IC₅₀ 63 nM) has a 4-dimethylaminobenzenesulfonyl side arm. One of the two side arms was varied with substituents in different positions. This gave a range of CD4 down-modulation potencies that correlated well with anti-HIV-1 activities. The side arms of 21 of the new benzyl-tailed analogues were modeled by means of quantum mechanical calculations. For CADA analogues with arenesulfonamide side arms, the pIC₅₀ values for CD4 down-modulation correlated with the component of the electric dipole moment in the aromatic ring, suggesting that an attractive electronic interaction is a major factor determining the stability of the complex between the molecule and its target.