Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent
Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent
复制标题
DOI：
10.1016/j.bmc.2010.04.011
复制
发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Sharma, Sunil K.
中科院分区：
文献类型：
--
作者：
Priya, Nivedita;Gupta, Anjali;Sharma, Sunil K.
我们已经研究了早期的膜结合的新酶乙酰氧基药物：蛋白质转乙酰酶鉴定为钙网蛋白转乙酰酶（CRTAase），催化乙酰基从多酚乙酸酯（PA）的受体蛋白的转移，从而调节其生物活性。本文首次报道了乙酰氧基喹诺酮类药物通过乙酰化作用激活血小板一氧化氮合酶（NOS），抑制ADP/花生四烯酸（AA）依赖性血小板聚集，从而具有抗血小板作用。血小板CRTAase对乙酰氧基喹诺酮类的各种类似物的特异性与细胞内NO和随后对血小板聚集抑制作用的相关性被认为是至关重要的。在筛选的乙酰氧基喹诺酮类化合物中，发现6-AQ（4-甲基-2-氧代-1，2-二氢喹啉-6-基乙酸酯/6-乙酰氧基喹啉-2-酮，22）是血小板CRTA酶的上级底物，并在体外和体内均成为产生抗血小板作用的最具活性的实体。6-AQ可抑制环氧化酶-1（考克斯-1）的表达，从而下调血栓素A2（TxA 2）的表达，抑制血小板聚集。结构模态乙酰氧基喹诺酮类阳离子与细胞内NO和抗血小板作用的增强呈正相关。(C)2010爱思唯尔有限公司版权所有。
We have studied earlier a membrane bound novel enzyme Acetoxy Drug: protein transacetylase identified as Calreticulin Transacetylase (CRTAase) that catalyzes the transfer of acetyl groups from polyphenolic acetates (PAs) to the receptor proteins and thus modulating their biological activities. In this communication, we have reported for the first time that acetoxy quinolones are endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. The correlation of specificity of platelet CRTAase to various analogues of acetoxy quinolones with intracellular NO and consequent effect on inhibition of platelet aggregation was considered crucial. Among acetoxy quinolones screened, 6-AQ (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate/6-acetoxyquinolin-2-one, 22) was found to be the superior substrate to platelet CRTAase and emerged as the most active entity to produce antiplatelet action both in vitro and in vivo. 6-AQ caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2) and the inhibition of platelet aggregation. Structural modi. cation of acetoxy quinolones positively correlated with enhancement of intracellular NO and antiplatelet action. (C) 2010 Elsevier Ltd. All rights reserved.