ZJM-289 is a potent racemic agent which inhibits both platelet aggregation and
thrombosis superior to a known anti-
ischemic stroke drug 3-n-butylphthalide (NBP). Herein, the enantiomers of
ZJM-289, (S)-ZJM-289 and (R)-ZJM-289, were synthesized and evaluated for their
biological activities. It was observed that the two enantiomers appeared to be almost as effective as
ZJM-289 in inhibiting platelet aggregation in vitro and
thrombus formation in vivo. Moreover, like
ZJM-289, its enantiomers could regulate the ratio of
thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α), and enhanced levels of
nitric oxide (NO), cAMP and cGMP, suggesting that the anti-platelet and antithrombotic activities of the enantiomers and
ZJM-289 are associated with both the
arachidonic acid cascade and cGMP-NO signal pathway. Furthermore, it was found that
oral administration of the enantiomers and
ZJM-289 for three days significantly reduced the
infarct size, brain water content and neurological deficit in rats after
cerebral ischemia reperfusion. Importantly, the two enantiomers equally improved blood flow in the
ischemic stroke model and modulated endothelial function through releasing moderate levels of NO, which might, at least partially, contribute to their neuroprotection. Collectively, the present study demonstrates that the two enantiomers are as potent as
ZJM-289 in inhibition of platelet aggregation and
thrombosis and in neuroprotection, and (S)-ZJM-289 shows somewhat better effects than (R)-ZJM-289 and
ZJM-289 in a few cases. These findings may provide new insights into the development of therapeutic agents like
ZJM-289 for the intervention of
thrombosis-related
ischemic stroke.