Zhao Ming, Bi Lanrong, Bi Wei, Wang Chao, Yang Zhe, Ju Jingfang, Peng Shiqi
College of Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing, 100054, PR China.
Bioorg Med Chem. 2006 Jul 15;14(14):4761-74. doi: 10.1016/j.bmc.2006.03.026. Epub 2006 Apr 17.
3-(S)-1,2,3,4-Tetrahydro-beta-carboline-3-carboxylic acid isolated from A. Chinese G. Don was found to possess moderate anti-aggregation activity, but with poor bioavailability. To improve its pharmacological property, we designed and synthesized a series of novel dipeptide analogues by incorporating tetrahydro-beta-carboline-3-carboxylic acid skeleton as an amino acid surrogate (*Trp). It turned out these dipeptide analogues exhibited good membrane permeability based on in vitro Caco-2 cell monolayers permeability assay. As a result, the overall biological properties of these molecules were significantly improved depending on the nature of the amino acid residues introduced onto the 3-position of the tetrahydro-beta-carboline moiety. It was very interesting to notice that these dipeptide analogues (5b,c,h,i,n,o,p,q) displayed a remarkable dual antiaggregatory activity in both of ADP- and PAF-induced platelet aggregation assay, and their aggregation response was significantly higher than that of aspirin (p<0.01). In addition, these dipeptide analogues were observed for the dose-dependent antithrombotic effect using in vivo rat arterial thrombosis model. The potency of antithrombotic activity of 5h,i,n,p was significantly higher than that of aspirin (n=12, p<0.01) at equal dose (5 micromol/kg).
从华千金藤中分离得到的3-(S)-1,2,3,4-四氢-β-咔啉-3-羧酸具有中等抗聚集活性，但生物利用度较差。为改善其药理性质，我们通过将四氢-β-咔啉-3-羧酸骨架作为氨基酸替代物（*Trp）设计并合成了一系列新型二肽类似物。基于体外Caco-2细胞单层通透性试验，结果表明这些二肽类似物表现出良好的膜通透性。因此，根据引入到四氢-β-咔啉部分3位上氨基酸残基的性质，这些分子的整体生物学性质得到了显著改善。非常有趣的是，这些二肽类似物（5b、c、h、i、n、o、p、q）在ADP和PAF诱导的血小板聚集试验中均表现出显著的双重抗聚集活性，且它们的聚集反应明显高于阿司匹林（p<0.01）。此外，使用体内大鼠动脉血栓形成模型观察到这些二肽类似物具有剂量依赖性抗血栓作用。在等剂量（5微摩尔/千克）时，5h、i、n、p的抗血栓活性效力明显高于阿司匹林（n = 12，p<0.01）。
