title: Studies toward novel peptidomimetic inhibitors of thioredoxin-thioredoxin reductase system.
abstract: Thioredoxins (Trx) are ubiquitous multifunctional low-molecular weight proteins that together with thioredoxin reductases (TrxR) participate in the maintenance of protein thiol homeostasis in NADPH-dependent reactions. An increasing number of data reveal that the Trx-TrxR system is an attractive target for anticancer therapies. In this work, we have elaborated a new and simple synthetic approach employing Ugi reaction to synthesize several new inhibitors of this system. The influence of various electrophilic fragments of this new class of compounds on the inhibition of the Trx-TrxR system was evaluated. As a result, a new compound 19a (SK053), which inhibits the activity of the Trx-TrxR system and exhibits antitumor activity, was obtained. Biologic analyses revealed that 19a inhibits induction of NF-κB and AP-1 and decreases H(2)O(2) scavenging capacity in tumor cells. Altogether, we show that 19a is a novel potential antitumor peptidomimetic inhibitor that can be used as a starting compound for further optimization.
authors: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors: Szymon
authors: S
authors: Kłossowski
authors: Angelika
authors: A
authors: Muchowicz
authors: Małgorzata
authors: M
authors: Firczuk
authors: Marta
authors: M
authors: Swiech
authors: Adam
authors: A
authors: Redzej
authors: Jakub
authors: J
authors: Golab
authors: Ryszard
authors: R
authors: Ostaszewski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008689:Methacrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014183:Transplantation, Heterologous
chemical_list: C570904:2,6-bis-trifluoromethylbenzoic acid 2-(1-(ethoxycarbonylmethylcarbamoyl)-3-methylbutylcarbamoyl)allyl ester; D000970:Antineoplastic Agents; D003603:Cytotoxins; D004151:Dipeptides; D016166:Free Radical Scavengers; D008689:Methacrylates; D016328:NF-kappa B; D057786:Peptidomimetics; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase