title: Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects.
abstract: 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.
authors.affiliation: Laboratory of General Chemistry, Department of Science, Agricultural University of Athens, Athens, Greece.
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Alexiou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.forename: Evangelos
authors.initials: E
authors.lastname: Ntougkos
authors.forename: Christos P
authors.initials: CP
authors.lastname: Papaneophytou
authors.forename: Fotini
authors.initials: F
authors.lastname: Liepouri
authors.forename: Anthi
authors.initials: A
authors.lastname: Mettou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Katsoulis
authors.forename: Anna
authors.initials: A
authors.lastname: Maranti
authors.forename: Katerina
authors.initials: K
authors.lastname: Tsiliouka
authors.forename: Alexandros
authors.initials: A
authors.lastname: Strongilos
authors.forename: Sotiria
authors.initials: S
authors.lastname: Chaitidou
authors.forename: Eleni
authors.initials: E
authors.lastname: Douni
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Elias
authors.initials: E
authors.lastname: Couladouros
authors.forename: Elias
authors.initials: E
authors.lastname: Eliopoulos
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D002839:Chromans; D007211:Indoles; D047888:Receptors, Tumor Necrosis Factor, Type I; C527814:SPD-304; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Inhibitors; Rational drug design; Synthesis