Rationally Designed Less Toxic SPD-304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects

被引：22

作者：

Alexiou, Polyxeni ^{[1
]}

Papakyriakou, Athanasios ^{[2
]}

Ntougkos, Evangelos ^{[3
]}

Papaneophytou, Christos P. ^{[4
,5
]}

Liepouri, Fotini ^{[6
]}

Mettou, Anthi ^{[4
,5
]}

Katsoulis, Ioannis ^{[6
]}

Maranti, Anna ^{[6
]}

Tsiliouka, Katerina ^{[6
]}

Strongilos, Alexandros ^{[6
]}

Chaitidou, Sotiria ^{[7
]}

Douni, Eleni ^{[2
,3
]}

Kontopidis, George ^{[4
,5
]}

Kollias, George ^{[3
]}

Couladouros, Elias ^{[1
]}

Eliopoulos, Elias ^{[2
]}

机构：

[1] Agr Univ Athens, Dept Sci, Lab Gen Chem, GR-11855 Athens, Greece

[2] Agr Univ Athens, Dept Biotechnol, Genet Lab, GR-11855 Athens, Greece

[3] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece

[4] Ctr Res & Technol Hellas CERTH, Inst Res & Technol Thessaly IRETETH, Volos, Greece

[5] Univ Thessaly, Sch Vet, Kardhitsa, Greece

[6] ProACTINA SA, Athens, Greece

[7] Pharmathen SA, Pharmaceut Ind, Athens, Greece

来源：

ARCHIV DER PHARMAZIE | 2014年 / 347卷 / 11期

关键词：

Inhibitors; Rational drug design; Synthesis; TUMOR-NECROSIS-FACTOR; RHEUMATOID-ARTHRITIS; ALPHA; PROTEIN; BINDING; DERIVATIVES; GENERATION; ALGORITHM; THERAPY;

D O I：

10.1002/ardp.201400198

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.

引用

页码：798 / 805

页数：8

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