Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity.
Protein tyrosine kinases have been known to be involved in regulation of platelet aggregation, suggesting a potential target for antiplatelet therapy. Our previous study showed that 3,4-methylenedioxy-beta-nitrostyrene (MNS) prevented platelet aggregation caused by various stimulators, and this action was accompanied by inhibition of tyrosine kinases. In the present study, in order to examine the structural determinants required for the actions of MNS and to develop more potent tyrosine kinase inhibitors and antiplatelet agents, a new series of beta-nitrostyrene derivatives were synthesized and pharmacologically characterized. The beta-nitrostyrene derivatives inhibited thrombin- or collagen-induced human platelet aggregation, ATP secretion, GPIIb/IIIa activation and protein tyrosine phosphorylation. In recombinant enzyme assay, some beta-nitrostyrene derivatives also demonstrated potent inhibition of Src and/or Syk kinase activity. Furthermore, there was a good correlation between the inhibitory potency of these compounds on tyrosine kinases and on platelet activation/aggregation. Among them, a benzoyl ester derivative (compound 10) possess up to 8-fold greater potency than MNS and over two orders of magnitude greater potency than genistein or tyrphostin A47 in inhibiting platelet responses to thrombin. Our data suggest that beta-nitrostyrenes may represent a new class of tyrosine kinase inhibitors with potent antiplatelet activity.
Wang
Wei-Ya
WY
Graduate Institute of Natural Products, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung City, Taiwan.
Hsieh
Pei-Wen
PW
Wu
Yang-Chang
YC
Wu
Chin-Chung
CC
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D015394:Molecular Structure; D009391:Nephelometry and Turbidimetry / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C514815:3,4-methylenedioxy-beta-nitrostyrene; D004148:Dioxolanes; D004791:Enzyme Inhibitors; D039661:Integrin beta3; D010975:Platelet Aggregation Inhibitors; D013343:Styrenes; D014443:Tyrosine; C011955:beta-nitrostyrene; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D019061:src-Family Kinases; D011493:Protein Kinase C; D002118:Calcium