Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors.
Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors.
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ICCA作为GPIIb/IIIa和P-选择素受体双重抑制剂的设计和开发
DOI：
10.2147/dddt.s169238
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhao M
中科院分区：
文献类型：
--
作者：
Chen H;Lu A;Zhang X;Gui L;Wang Y;Wu J;Feng H;Peng S;Zhao M
血小板膜糖蛋白（GP）IIb/IIIa和P-选择素的上调对动脉血栓形成、静脉血栓形成和癌症的发生的影响促使人们假设GPIIb/IIIa和P-选择素受体的双重抑制剂应该同时抑制动脉血栓形成、阻断静脉血栓形成和减缓肿瘤生长。方法分析了12种咔啉类化合物的结构特征和CDOCKER相互作用能。这导致设计1-（4-异丙基-苯基）-β-咔啉-3-羧酸（ICCA）作为GPIIb/IIIa和P-选择素受体的有希望的抑制剂。结果合成路线总收率48%，高效液相色谱纯度99.6%。在体内5 μmol/kg口服ICCA下调GPIIb/IIIa和P-选择素表达，从而抑制动脉血栓形成，阻断静脉血栓形成，减缓肿瘤生长，但不损害肾脏和肝脏。结论ICCA具有下调GPIIb/IIIa和P-选择素受体，抑制动脉血栓形成，阻断静脉血栓形成，延缓肿瘤生长的作用。
Background The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. Methods For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-β-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors. Results The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. Conclusion Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.