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Title: Antiplatelet Activities of Newly Synthesized Derivatives of Piperlongumine

Author
item PARK, BYEOUNG-SOO - NAKYUNG UNIV., KOREA
item SON, DONG-JU - CHUNGBIK UNIV., KOREA
item CHOI, WONG-SIK - SOONCHUNHYANG UNIV., KORE
item Takeoka, Gary
item HAN, SUNG OK - KOREA UNIV., SEOUL, KOREA
item KIM, TAE-WAN - HANKYONG UNIV., KOREA
item LEE, SUNG-EUN - NANOTOXTECH INC., KOREA

Submitted to: Phytotherapy Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/19/2008
Publication Date: 8/11/2008
Citation: Park, B-S., Son, D-J., Choi, W-S., Takeoka, G.R., Han, S.O., Kim, T-W., Lee, S-E. 2008. Antiplatelet Activities of Newly Synthesized Derivatives of Piperlongumine. Phytotherapy Research. DOI: 10.1002/ptr.2432.

Interpretive Summary: Cardiovascular diseases are the leading cause of death in developed countries and are progressively increasing their impact on mortality in developing countries despite changes in lifestyle and the use of preventative pharmacological approaches. Blood is normally not aggregated in the blood vessels but on an occasion of bleeding, blood aggregation is generated as a physiological defense reaction. Platelet aggregation is caused by physiological substances such as PAF, thrombin and protoglandin endoperoxide and can lead to arterial thrombosis. Inhibitors of platelet aggregation can provide protection against acute coronary syndromes. In this study we found that piperine, pipernonaline, piperoctadecalidine and piperlongumine, four alkaloids derived from P. longum L., inhibited in vitro rabbit platelet aggregation induced by collagen, AA and PAF. These results suggested that long pepper constituents may be useful as lead materials and new agents for the prevention and treatment of cardiovascular diseases such as thrombosis. Seven new compounds, structurally related to piperlongumine, were synthesized and their antiplatelet activity was found to vary in relationship to their structure.

Technical Abstract: Piperlongumine, a pyridine alkaloid isolated from Piper longum L., exhibited a potential inhibitory effect on washed rabbit platelet aggregation induced by collagen, arachidonic acid (AA) and platelet activating factor (PAF), without affecting that induced by thrombin. Piperlongumine was used as a lead compound for the synthesis of new antiplatelet agents. Seven synthetic compounds were newly synthesized from 3,4,5-trimethoxycinnamic acid (TMCA). They were 1-piperidin-1-yl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1’), 1-morpholin-4-yl-3-(3,4,5-trimethoxyphenyl)pro-2-en-1-one (2’), 1-(3,5-dimethylpiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)pro-2-en-1-one (3’), 1-(2-methylpiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4’), 1-(3-hydroxypiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5’), 1-[3-(3,4,5-trimethoxyphenyl)acryloyl]piperidin-2-one (6’), and ethyl 1-[3-(3,4,5-trimethoxyphenyl)acryloyl]piperidine-4-carboxylate (7’). Among those seven synthetic derivatives, 1-(3,5-dimethylpiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)pro-2-en-1-one (3’) had the most potent inhibitory effect on platelet aggregation induced by collagen, AA-, and PAF.