NP‐313, 2‐acetylamino‐3‐chloro‐1,4‐naphthoquinone, a novel antithrombotic agent with dual inhibition of thromboxane A₂ synthesis and calcium entry

Abstract

BACKGROUND AND PURPOSE1,4-Naphthoquinones exhibit antiplatelet activity both in vivo and in vitro. In the present study, we investigated the antiplatelet effect of a novel naphthoquinone derivative NP-313, 2-acetylamino-3-chloro-1,4-naphthoquinone and its mechanism of action. EXPERIMENTAL APPROACHWe measured platelet aggregation, Ca 2+ mobilization, thromboxane B2 formation and P-selectin expression and examined several enzymatic activities. Furthermore, we used the irradiated mesenteric venules in fluorescein sodium-treated mice to monitor the antithrombotic effect of NP-313 in vivo. KEY RESULTSNP-313 concentration-dependently inhibited human platelet aggregation induced by collagen, arachidonic acid, thapsigargin, thrombin and A23187. NP-313 also inhibited P-selectin expression, thromboxane B2 formation and [Ca 2+ ]i elevation in platelets stimulated by thrombin and collagen. NP-313 at 10 mM inhibited cyclooxygenase, thromboxane A2 synthase, and protein kinase Ca, whereas it did not affect phospholipase A2 or phospholipase C activity. In the presence of indomethacin and an adenosine 5-diphosphate scavenger, NP-313 concentration-dependently inhibited thrombin-and A23187-induced [Ca 2+ ]i increase through its inhibitory effects on Ca 2+ influx, rather than blocking Ca 2+ release from intracellular stores. NP-313 also inhibited thapsigargin-mediated Ca 2+ influx through store-operated calcium channel but had no effect on Ca 2+ influx through store-independent calcium channel evoked by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol. Nevertheless, it had little effect on cyclic AMP and cyclic GMP levels. Also, intravenously administered NP-313 dose-dependently inhibited the thrombus occlusion of the irradiated mesenteric vessels of fluorescein-pretreated mice.

Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

“…It contains two ketone groups as crucial moieties, which are responsible for many biological activities because of their abilities to accept electrons (Benites et al, 2010[ 2 ]; O'Brien, 1991[ 32 ]). Various biological activities of 1,4-naphthoquinone derivatives have been reported, i.e., anticancer (Kishore et al, 2014[ 20 ]; Mallavadhani et al, 2014[ 26 ]; Nasiri et al, 2013[ 31 ]; Prachayasittikul et al, 2014[ 35 ]; Sreelatha et al, 2014[ 42 ]), radical scavenging (Kumar et al, 2013[ 21 ]; Lebedev et al, 2008[ 24 ]; Song et al, 2000[ 40 ]), antimicrobial (Ryu and Kim, 1992[ 37 ]; Sreelatha et al, 2014[ 42 ]; Tandon et al, 2009[ 45 ]), antiviral (Crosby et al, 2011[ 9 ]; Da Costa et al, 2013[ 10 ]; Ilina et al, 2002[ 16 ]), antifungal (Castro et al, 2013[ 6 ]; Pawar et al, 2014[ 33 ]; Tandon et al, 2009[ 45 ]), antitrypanocidal (Salmon-Chemin et al, 2001[ 38 ]) and antiplatelet (Jin et al, 2004[ 17 ]; Kuo et al, 2011[ 22 ]; Lien et al, 2002[ 25 ]; Yuk et al, 2000[ 48 ]) activities. It was found that structural modification can effectively modulate the electrochemical behavior of 1,4-naphthoquinone compounds, thereby affecting their biological activities (Hillard et al, 2008[ 15 ]).…”