Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships

Polucci P.; Magnaghi P.; Angiolini M.; Asa D.; Avanzi N.; Badari A.; Bertrand J.; Casale E.; Cauteruccio S.; Cirla A.; Cozzi L.; Galvani A.; Jackson P.K.; Liu Y.; Magnuson S.; Malgesini B.; Nuvoloni S.; Orrenius C.; Sirtori F.R.; Riceputi L.; Rizzi S.; Trucchi B.; OBrien T.; Isacchi A.; Donati D.

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Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships

机译：烷基硫烷基1,2,4-三唑，一种新型的变构缬氨酸，含蛋白质抑制剂。合成与构效关系

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Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

机译：含缬氨酸的蛋白质（VCP），也称为p97，是AAA ATPase家族的成员，该家族参与多个生物学过程，并在遍在蛋白介导的错折叠蛋白降解中发挥重要作用。 VCP是一种普遍表达的，高度丰富的蛋白质，已发现在许多肿瘤类型中过表达，有时与不良预后有关。在这方面，VCP最近作为癌症治疗的潜在新靶标受到了广泛关注。在本文中，描述了新型强效变构VCP抑制剂烷基硫烷基-1,2,4-三唑的发现及其与构效关系。通过HTS鉴定的化合物1的药物化学操作导致发现了有效和选择性的抑制剂，这些抑制剂在细胞中具有亚微摩尔活性，并且在恒定剂量下具有明确的作用机理。这代表了迈向新型潜在抗癌药的第一步。

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《Journal of Medicinal Chemistry》 |2013年第2期|共14页
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Polucci P.; Magnaghi P.; Angiolini M.; Asa D.; Avanzi N.; Badari A.; Bertrand J.; Casale E.; Cauteruccio S.; Cirla A.; Cozzi L.; Galvani A.; Jackson P.K.; Liu Y.; Magnuson S.; Malgesini B.; Nuvoloni S.; Orrenius C.; Sirtori F.R.; Riceputi L.; Rizzi S.; Trucchi B.; OBrien T.; Isacchi A.; Donati D.;
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1. Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships [J] . Polucci P., Magnaghi P., Angiolini M., Journal of Medicinal Chemistry . 2013,第2期

机译：烷基硫烷基1,2,4-三唑，一种新型的变构缬氨酸，含蛋白质抑制剂。合成与构效关系
2. Structure-activity relationships for NAMI-A-type complexes (HL)[trans-RuCl4L(S-dmso)ruthenate(III)] (L = imidazole, indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole): Aquation, redox properties, protein binding, and antip [J] . Groessl M, Reisner E, Hartinger CG, Journal of Medicinal Chemistry . 2007,第9期

机译：NAMI-A型配合物（HL）[反式RuCl4L（S-dmso）钌（III）]的结构活性关系（L =咪唑，吲唑，1,2,4-三唑，4-氨基-1,2 ，4-三唑和1-甲基-1,2,4-三唑）：水合，氧化还原特性，蛋白质结合和抗氧化剂
3. Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series. [J] . Song Y, Connor DT, Sercel AD, Journal of Medicinal Chemistry . 1999,第7期

机译：合成，结构-活性关系以及取代的二叔丁基苯酚作为一类新型的有效，选择性和口服活性环氧合酶2抑制剂的体内评价。 2. 1,3,4-和1,2,4-噻二唑系列。
4. Synthesis of a Novel Class of Aza Crown Macrocycles Containing Two 1,2,4-Triazole Rings as Subunits [C] . Sattar Ebrahimi, Naser Foroughifar, Akbar Mobinikhaledi European Symposium on Organic Chemistry . 2009

机译：一种新型AZA冠癌癌的组合，其中包含两个1,2,4-三唑环作为亚基
5. Part I. The synthesis and structure-activity relationship study of azo dye related HIV replication inhibitors. Part II. Plant isolation of signalling pathways inhibitors as anti-cancer agents. [D] . Lu, Hang. 1994

机译：第一部分：偶氮染料相关的HIV复制抑制剂的合成及其构效关系研究。第二部分植物分离的信号通路抑制剂为抗癌剂。
6. Synthesis and Structure-Activity Relationship Studies of Conformationally Flexible Tetrahydroisoquinolinyl Triazole Carboxamide and Triazole Substituted Benzamide Analogues as σ2 Receptor Ligands [O] . Suping Bai, Shihong Li, Jinbin Xu, -1

机译：构型柔性四氢异喹啉基三唑羧酰胺和三唑取代的苯甲酰胺类似物作为σ2受体配体的合成及结构活性关系研究
7. Design of new potent and selective secretory phospholipase A2 inhibitors. 6 - Synthesis, structure-activity relationships and molecular modelling of 1-substituted-4-[4,5-dihydro-1,2,4-(4H)-oxadiazol-5-one-3-yl(methyl)]-functionalized aryl piperazin/one/dione derivatives [O] . Meddad-Belhabich, Nadia, Aoun, Darina, Djimdé, Atimé, 2010

机译：新的有效和选择性分泌型磷脂酶A2抑制剂的设计。 6-功能化的1-取代-4- [4,5-二氢-1,2,4-（4H）-恶二唑-5-一-3-基（甲基）]的合成，构效关系和分子模型芳基哌嗪/一/二酮衍生物

Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships

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