Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation

Yi Chang, Wen Hsien Hsu, Wen Bin Yang, Thanasekaran Jayakumar, Tzu Yin Lee, Joen Rong Sheu, Wan Jung Lu, Jiun Yi Li

Research output: Contribution to journalArticle

Abstract

Antiplatelet agents have considerable benefits in the treatment of thromboembolic diseases; however, these agents still have substantial limitations due to their severe side-effects. In this study, the antiplatelet activity of three newly synthesized saccharide based benzimidazole derivatives, M3BIM, Malto-BIM and Melibio-BIM, in collagen and thrombin-stimulated human platelets in vitro was examined. Among the compounds tested, only compound M3BIM exerted concentration (20-60 μM)-dependent inhibitory effects against collagen (1 μg/ml) and thrombin (0.01 U/ml)-induced washed human platelet aggregation. Moreover, at a concentration of 60 μM, M3BIM distinctly abolished collagen-induced adenosine triphosphate (ATP) release and intracellular Ca2+ mobilization. Additionally, this compound attenuated the collagen-induced phosphorylation of p47, a marker of the activation of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK). However, Malto-BIM and Melibio-BIM were not effective in this regard. Moreover, the toxic effects of these compounds were evaluated using zebrafish embryo toxicity (ZET) assay, and the results revealed that all three compounds had no comparative cytotoxicity within the range of 25-200 μM. Overall, the results of this study provide evidence for the inhibitory effects of M3BIM on collagen-induced platelet aggregation in vitro compared to other imidazole derivatives. The presence of 1-imidazolyl moiety at one end with a longer chain length (three sugar moieties) may be mainly responsible for the observed effects of M3BIM. These results suggest that compound M3BIM may be used as a potential candidate for the treatment of aberrant platelet activation-related diseases as it inhibits the activation of p47 and p38 MAPK, and reduces ATP release and Ca2+ mobilization.

Original languageEnglish
Pages (from-to)1520-1528
Number of pages9
JournalInternational Journal of Molecular Medicine
Volume40
Issue number5
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Platelet Activation
Structure-Activity Relationship
Oligosaccharides
Collagen
p38 Mitogen-Activated Protein Kinases
Platelet Aggregation
Thrombin
Adenosine Triphosphate
Poisons
Platelet Aggregation Inhibitors
Zebrafish
Protein Kinase C
Blood Platelets
Embryonic Structures
Phosphorylation
benzimidazole
In Vitro Techniques

Keywords

  • Adenosine triphosphate
  • Antiaggregant effect
  • Benzimidazole
  • Ca
  • P38 mitogenactivated protein kinase/p47
  • Zebrafish

ASJC Scopus subject areas

  • Genetics

Cite this

Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation. / Chang, Yi; Hsu, Wen Hsien; Yang, Wen Bin; Jayakumar, Thanasekaran; Lee, Tzu Yin; Sheu, Joen Rong; Lu, Wan Jung; Li, Jiun Yi.

In: International Journal of Molecular Medicine, Vol. 40, No. 5, 01.11.2017, p. 1520-1528.

Research output: Contribution to journalArticle

Chang, Yi ; Hsu, Wen Hsien ; Yang, Wen Bin ; Jayakumar, Thanasekaran ; Lee, Tzu Yin ; Sheu, Joen Rong ; Lu, Wan Jung ; Li, Jiun Yi. / Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation. In: International Journal of Molecular Medicine. 2017 ; Vol. 40, No. 5. pp. 1520-1528.
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AU - Lee, Tzu Yin

AU - Sheu, Joen Rong

AU - Lu, Wan Jung

AU - Li, Jiun Yi

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