Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 11; pp. 4085 - 4094
• Main Authors: Priya, Nivedita, Gupta, Anjali, Chand, Karam, Singh, Prabhjot, Kathuria, Abha, Raj, Hanumantharao G., Parmar, Virinder S., Sharma, Sunil K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2010; Elsevier
• Subjects: Acetates; Acetyltransferases - metabolism; Antiplatelet agents; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cox-1; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Down-Regulation; Humans; Medical sciences; Nitric Oxide; Nitric Oxide Synthase - metabolism; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemistry; Platelet CRTAase; Quinolin-2-ones; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; Substrate Specificity; Thromboxane A2 - biosynthesis; AA; NO; PAs; Quinolin-2-ones; GST; CDNB; DAMC; PRP; AQ; DCFH-DA; PPP; TxA2; NOS; TxB2; Platelet CRTAase; Cox-1; Cox-2; CRTAase; GSH; Antiplatelet agents; Acyltransferases; Flow cytometry; Enzyme; Transferases; Cyclooxygenase 1; Quinoline derivatives; Anticoagulant; In vitro; Biological activity; Antiplatelet agent; Platelet; Oxidoreductases; Mechanism of action; Chemical synthesis; Quinolone derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.011

A series of novel quinolin-2-one derivatives were synthesized and examined for their antiplatelet action by virtue of causing Calreticulin Transacetylase catalyzed activation of platelet Nitric Oxide Synthase. 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 modification of acetoxy quinolones positively correlated with enhancement of intracellular NO and antiplatelet action.