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Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-09 , DOI: 10.1016/j.bmc.2019.115216 Dimitrios Triantafyllos Gerokonstantis 1 , Aikaterini Nikolaou 1 , Christiana Magkrioti 2 , Antreas Afantitis 3 , Vassilis Aidinis 2 , George Kokotos 1 , Panagiota Moutevelis-Minakakis 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-09 , DOI: 10.1016/j.bmc.2019.115216 Dimitrios Triantafyllos Gerokonstantis 1 , Aikaterini Nikolaou 1 , Christiana Magkrioti 2 , Antreas Afantitis 3 , Vassilis Aidinis 2 , George Kokotos 1 , Panagiota Moutevelis-Minakakis 1
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Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX.
中文翻译：
新型2-吡咯烷酮和吡咯烷衍生物的合成及其对自分泌运动抑制酶的抑制作用研究。
自黑素（ATX）是一种从黑素瘤细胞中分离为自分泌运动因子的糖蛋白（〜125 kDa），属于外核苷酸焦磷酸酶/磷酸二酯酶（ENPP）的七元家族，并具有溶血磷脂酶D的活性。ATX负责溶血磷脂酰胆碱（LPC）的水解以产生具有生物活性的脂质溶血磷脂酸（LPA），其在多种病理性炎症条件（包括纤维化，癌症，肝毒性和血栓形成）中被上调。鉴于其在人类疾病中的作用，ATX-LPA轴是一个有趣的治疗靶标，新型有效ATX抑制剂的开发非常重要。在本工作中，合成了新型的ATX抑制剂，2-吡咯烷酮和吡咯烷杂环的光学活性衍生物。
更新日期：2019-12-11
中文翻译：
新型2-吡咯烷酮和吡咯烷衍生物的合成及其对自分泌运动抑制酶的抑制作用研究。
自黑素（ATX）是一种从黑素瘤细胞中分离为自分泌运动因子的糖蛋白（〜125 kDa），属于外核苷酸焦磷酸酶/磷酸二酯酶（ENPP）的七元家族，并具有溶血磷脂酶D的活性。ATX负责溶血磷脂酰胆碱（LPC）的水解以产生具有生物活性的脂质溶血磷脂酸（LPA），其在多种病理性炎症条件（包括纤维化，癌症，肝毒性和血栓形成）中被上调。鉴于其在人类疾病中的作用，ATX-LPA轴是一个有趣的治疗靶标，新型有效ATX抑制剂的开发非常重要。在本工作中，合成了新型的ATX抑制剂，2-吡咯烷酮和吡咯烷杂环的光学活性衍生物。
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