title: Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent.
abstract: 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.
authors.affiliation: Department of Biochemistry, V P Chest Institute, University of Delhi, Delhi 110 007, India.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Priya
authors.forename: Anjali
authors.initials: A
authors.lastname: Gupta
authors.forename: Karam
authors.initials: K
authors.lastname: Chand
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Singh
authors.forename: Abha
authors.initials: A
authors.lastname: Kathuria
authors.forename: Hanumantharao G
authors.initials: HG
authors.lastname: Raj
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
mesh_terms: D000085:Acetates; D000123:Acetyltransferases / Q000378:metabolism; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors; D015536:Down-Regulation; D006801:Humans; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013928:Thromboxane A2 / Q000096:biosynthesis
chemical_list: D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D009569:Nitric Oxide; D013928:Thromboxane A2; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D000123:Acetyltransferases; C539012:calreticulin transacetylase, human