Wei Ya Wang

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Binding fibrinogen to activated glycoprotein (GP)IIb/IIIa is the final common pathway of platelet aggregation and has become a successful target for antiplatelet therapy. In the present study, we found that a small chemical compound, 3,4-methyl-enedioxy-β-nitrostyrene (MNS), exhibited potent and broad-spectrum inhibitory effects on human platelet aggregation caused by various stimulators. Moreover, addition of MNS to human platelets that had been aggregated by ADP caused a rapid disaggregation. We demonstrated that the antiaggregatory activity of MNS is due to inhibition of GPIIb/IIIa activation by measuring the binding amount of PAC-1 in platelets. In contrast, MNS is not a direct antagonist of GPIIb/IIIa, because MNS did not affect fibrinogen binding to fixed ADP-stimulated platelets. By investigating how MNS inhibits GPIIb/IIIa activation, we found that MNS potently inhibited the activity of tyrosine kinases (Src and Syk) and prevented protein tyrosine phosphorylation and cytoskeletal association of GPIIb/IIIa and talin, but it had no direct effects on protein kinase C, Ca2+ mobilization, Ca2+-dependent enzymes (myosin light chain kinase and calpain), and arachidonic acid metabolism, and it did not affect the cellular levels of cyclic nucleotides. Therefore, MNS represents a new class of tyrosine kinase inhibitor that potently prevents GPIIb/IIIa activation and platelet aggregation without directly affecting other signaling pathways required for platelet activation. Because MNS inhibits GPIIb/IIIa functions in a manner different from GPIIb/IIIa antagonists, this feature may provide a new strategy for treatment of platelet-dependent thrombosis.

Antiplatelet activity of benzylisoquinoline derivatives oxidized by cerium(IV) ammonium nitrate.

Oxidation of 1-benzyl-3,4-dihydroisoquinolines with cerium(IV) ammonium nitrate (CAN) under mild condition yielded the mixture of corresponding 1-benzylisoquinolines (b-type) and 1-benzoylisoquinolines (a- or c-type) in an equal yields. The selective oxidation products (c-type) can be prepared by using MeCN instead of MeOH. In the antiplatelet assays, four inducers were employed, including AA, Col, PAF, and Thr. In the PAF or Col induced platelet aggregation, compounds belonging to a- and b-type showed stronger inhibitory effects than aspirin.

Effect of active synthetic 2-substituted quinazolinones on anti-platelet aggregation and the inhibition of superoxide anion generation by neutrophils.

Quinazolinones, 2-substituted and 3-substituted, mainly synthesized by microwave irradiation, were subjected to anti-platelet aggregation and inhibition of superoxide anion generation assays. Interestingly, 2-phenyl-4-quinazolinone (4) exhibited significant inhibitory activities toward platelet aggregation and neutrophil activation, and it might therefore serve as a prototype lead compound.