title: Substrate specificity of acetoxy derivatives of coumarins and quinolones towards Calreticulin mediated transacetylation: investigations on antiplatelet function.
abstract: Calreticulin transacetylase (CRTAase) is known to catalyze the transfer of acetyl group from polyphenolic acetates (PA) to certain receptor proteins (RP), thus modulating their activity. Herein, we studied for the first time the substrate specificity of CRTAase towards N-acetylamino derivatives of coumarins and quinolones. This study is 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. Among all the N-acetylamino/acetoxy coumarins and quinolones screened, 7-N-acetylamino-4-methylcoumarin (7-AAMC, 17) was found to be the superior substrate to platelet CRTAase and emerged as the most promising antiplatelet agent both in vitro and in vivo. Further it caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2), modulation of tissue factor and the inhibition of platelet aggregation. It was also found effective in the inhibition of LPS induced pro-thrombotic conditions.
authors.affiliation: Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
authors.forename: Abha
authors.initials: A
authors.lastname: Kathuria
authors.forename: Nivedita
authors.initials: N
authors.lastname: Priya
authors.forename: Karam
authors.initials: K
authors.lastname: Chand
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Singh
authors.forename: Anjali
authors.initials: A
authors.lastname: Gupta
authors.forename: Sarah
authors.initials: S
authors.lastname: Jalal
authors.forename: Shilpi
authors.initials: S
authors.lastname: Gupta
authors.forename: Hanumantharao G
authors.initials: HG
authors.lastname: Raj
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059808:Polyphenols / Q000737:chemistry*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013379:Substrate Specificity
chemical_list: C572566:7-N-acetylamino-4-methylcoumarin; D003374:Coumarins; D010975:Platelet Aggregation Inhibitors; D059808:Polyphenols; D011804:Quinolines