3-4-methylenedioxy-beta-nitrostyrene and beta-nitrostyrene

Our previous studies demonstrated that two cytotoxic β-nitrostyrene derivatives, 3,4-methylenedioxy-β-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy-β-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of β-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC(50)≤0.7 μM) without significant cytotoxicity on a human cancer cell line (up to 20 μM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents.

Topics: Cell Line, Tumor; Humans; Integrin beta3; Platelet Aggregation; Platelet Aggregation Inhibitors; Structure-Activity Relationship; Styrenes

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The beta-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the beta-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC(50) of <10 microM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.

Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Fungi; Humans; Molecular Structure; Resveratrol; Stilbenes; Structure-Activity Relationship; Styrenes; Tubulin; Tubulin Modulators

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.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Blood Platelets; Blotting, Western; Calcium; Dioxolanes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flow Cytometry; Humans; Integrin beta3; Molecular Structure; Nephelometry and Turbidimetry; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Kinase C; src-Family Kinases; Structure-Activity Relationship; Styrenes; Tyrosine