KIN-59
(Synonyms: 5'-O-三苯甲基-肌苷,5’-O-Tritylinosine) 目录号 : GC16460KIN-59是针对人源和细菌重组胸苷磷酸化酶（TPase）的非竞争性抑制剂，IC50值分别为67和44µM。
Cas No.:4152-77-6
Sample solution is provided at 25 µL, 10mM.
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KIN-59 is a noncompetitive inhibitor against human and bacterial recombinant thymidine phosphorylase (TPase) with IC50 values of 67 and 44µM respectively[1]. KIN-59 is a purine riboside derivative that blocks the enzyme non-competitively with thymidine or phosphate, and requires both the intact 5′-O-trityl group and the ribose–hypoxanthine scaffold for activity[2].
In vitro, KIN-59 (0–100µM) incubated muse aortic endothelial cells (MAECs) for 5 days poorly inhibited cell proliferation with an IC50 value of 78 ± 2µM. KIN-59 also dose-dependently slowed endothelial cell migration in a 16-hour wound-healing assay[3]. KIN-59 (250nmol) incubated fertilized chicken eggs with or without 10µl of TPase for 4 days. KIN-59 not only annihilated the TPase-induced angiogenesis but also efficiently inhibited the formation of normal chick chorioallantoic membrane vessels in the absence of exogenously added TPase[4]. KIN-59 (125–250μM) pretreatment on human or wild-type murine platelets for 5min before collagen, ADP, thrombin or collagen related peptide stimulation reversibly and dose-dependently suppressed induced aggregation[5].
In vivo, KIN-59 (15mg/kg) was injected subcutaneously in immunodeficient nude mice twice daily (once daily during the weekend) until day 20. KIN-59 inhibited the binding of fibroblast growth factor 2 (FGF2) to FGF receptor 1, preventing the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells[6].
References:
[1] Liekens S, Balzarini J, Hernández A I, et al. Thymidine phosphorylase is noncompetitively inhibited by 5'-O-trityl-inosine (KIN59) and related compounds. Nucleosides Nucleotides Nucleic Acids. 2006;25(9-11):975-80.
[2] Casanova E, Hernandez A I, Priego E M, et al. 5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase. J Med Chem. 2006 Sep 7;49(18):5562-70.
[3] Liekens, S., Bronckaers, A., Hernández, A.I., et al. 5'-O-tritylated nucleoside derivatives: inhibition of thymidine phosphorylase and angiogenesis. Mol. Pharmacol. 70(2), 501-509 (2006).
[4] Liekens, S., Hernández, A.I., Ribatti, D., et al. The nucleoside derivative 5'-O-trityl-inosine (KIN59) suppresses thymidine phosphorylase-triggered angiogenesis via a noncompetitive mechanism of action. The Journal of Biological Chemisty 279(28), 29598-29605 (2004).
[5] Li W, Gigante A, Perez-Perez M J, et al. Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ Res. 2014 Dec 5;115(12):997-1006.
[6] Liekens, S., Bronckaers, A., Belleri, M., et al. The thymidine phosphorylase inhibitor 5'-O-tritylinosine (KIN-59) is an antiangiogenic multitarget fibroblast growth factor-2 antagonist. Mol. Cancer Ther. 11(4), 817-829 (2012).
KIN-59是针对人源和细菌重组胸苷磷酸化酶（TPase）的非竞争性抑制剂，IC50值分别为67和44µM[1]。KIN-59是一种嘌呤核糖衍生物，能以非竞争性方式阻断酶与胸苷或磷酸的结合，其活性依赖于完整的5′-O-三苯甲基和核糖-次黄嘌呤骨架[2]。
体外实验中，KIN-59（0–100µM）孵育小鼠主动脉内皮细胞（MAECs）5天，对细胞增殖的抑制作用较弱，IC50值为78 ± 2µM。KIN-59在16小时划痕愈合实验中也呈剂量依赖性地减缓内皮细胞迁移[3]。KIN-59（250nmol）单独或与10µl TPase共同孵育受精鸡蛋4天，KIN-59不仅消除了TPase诱导的血管生成，还有效抑制了无外源TPase存在时正常鸡胚绒毛尿囊膜血管的形成[4]。KIN-59（125–250µM）在人或野生型小鼠血小板中加入胶原、ADP、凝血酶或胶原相关肽前预处理5分钟。KIN-59可逆且呈剂量依赖性地抑制诱导的血小板聚集[5]。
体内实验中，KIN-59（15mg/kg）通过皮下注射免疫缺陷裸鼠，每日两次（周末每日一次），持续至第20天。KIN-59抑制成纤维细胞生长因子2（FGF2）与FGF受体1的结合，阻止由FGF2转化的内皮细胞诱导的皮下肿瘤生长和新生血管形成[6]。
| Kinase experiment [1]: | |
Preparation Method | 500μL reaction solution containing 10mM Tris-HCl pH 7.6, 1mM EDTA, 150mM NaCl, 2mM phosphate and 100μM thymidine with 0.025U enzyme TPase was incubated for 60min at room temperature. The samples taken at 0, 20, 40, 60min, 100μL aliquots were boiled, cooled and analyzed by RP-8 HPLC (267nm) to quantify thymine formation. KIN-59 (1mM, 100μM, 10μM, and 0μM) were added to the reaction mixture to test for TPase inhibition. |
Reaction Conditions | 0–1000μM; 60min |
Applications | KIN-59 inhibited TPase in a reversible, non-competitive manner with Ki value of about 39μM. |
| Cell experiment [2]: | |
Cell lines | Fetal bovine aortic endothelial GM7373 cells |
Preparation Method | Serum-starved FGFR1-overexpressing GM7373 cells and VEGFR2-overexpressing GM7373 cells were incubated with 60μM KIN-59 or vehicle for 30min, after which 10ng/mL FGF2 or 30ng/mL VEGF was added. |
Reaction Conditions | 60μM; 30min |
Applications | KIN-59 inhibited FGF2- but not VEGF-stimulated endothelial cell growth. |
| Animal experiment [2]: | |
Animal models | Female, athymic, nude nu/nu mice |
Preparation Method | Eight-week-old female, athymic, nude nu/nu mice, weighing about 25g, were inoculated subcutaneously with 200mL of serum-free DMEM containing 2×106 F2T-luc2.9 cells. KIN-59 treatment was started after 24 hours and continued till the end of the experiment. KIN-59 was administered subcutaneously at 15mg/kg, twice daily (once daily during the weekend) at a site distant from the tumor (inoculation) site. |
Dosage form | 15mg/kg; s.c; twice daily (once daily during the weekend) |
Applications | KIN-59 inhibited the binding of fibroblast growth factor 2 (FGF2) to FGF receptor 1, preventing the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells. |
References: | |
| Cas No. | 4152-77-6 | SDF | |
| 别名 | 5'-O-三苯甲基-肌苷,5’-O-Tritylinosine | ||
| 化学名 | 5'-O-(triphenylmethyl)-inosine | ||
| Canonical SMILES | O[C@H]1[C@@H](O)[C@H](N2C=NC3=C2N=CNC3=O)O[C@@H]1COC(C4=CC=CC=C4)(C5=CC=CC=C5)C6=CC=CC=C6 | ||
| 分子式 | C29H26N4O5 | 分子量 | 510.5 |
| 溶解度 | ≤0.3mg/ml in ethanol;16mg/ml in DMSO;5mg/ml in dimethyl formamide | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9589 mL | 9.7943 mL | 19.5886 mL |
| 5 mM | 391.8 μL | 1.9589 mL | 3.9177 mL |
| 10 mM | 195.9 μL | 979.4 μL | 1.9589 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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