Chen Haiyan, Lu An, Zhang Xiaoyi, Gui Lin, Wang Yaonan, Wu Jianhui, Feng Hua, Peng Shiqi, Zhao Ming
Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People's Republic of China,
Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan,
Drug Des Devel Ther. 2018 Jul 9;12:2097-2110. doi: 10.2147/DDDT.S169238. eCollection 2018.
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.
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)--carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors.
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.
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.
血小板膜糖蛋白（GP）IIb/IIIa和P-选择素上调对动脉血栓形成、静脉血栓形成及癌症发病的影响促使人们推测，GPIIb/IIIa和P-选择素受体双重抑制剂应能同时抑制动脉血栓形成、阻断静脉血栓形成并减缓肿瘤生长。
因此，分析了12种咔啉的结构特征及CDOCKER相互作用能。据此设计了1-（4-异丙基苯基）-β-咔啉-3-羧酸（ICCA），作为一种有前景的GPIIb/IIIa和P-选择素受体抑制剂。
合成路线得到的ICCA总收率为48%，高效液相色谱纯度为99.6%。在体内，5 μmol/kg口服ICCA可下调GPIIb/IIIa和P-选择素表达，从而抑制动脉血栓形成、阻断静脉血栓形成并减缓肿瘤生长，但不损害肾脏和肝脏。
因此，ICCA可能是一种有前景的候选药物，能够下调GPIIb/IIIa和P-选择素受体，抑制动脉血栓形成、阻断静脉血栓形成并减缓肿瘤生长。
