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Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-03 , DOI: 10.1016/j.ejmech.2020.112112 Andrea Petreni 1 , Alessandro Bonardi 1 , Carrie Lomelino 2 , Sameh M Osman 3 , Zeid A ALOthman 3 , Wagdy M Eldehna 4 , Radwan El-Haggar 5 , Robert McKenna 2 , Alessio Nocentini 1 , Claudiu T Supuran 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-03 , DOI: 10.1016/j.ejmech.2020.112112 Andrea Petreni 1 , Alessandro Bonardi 1 , Carrie Lomelino 2 , Sameh M Osman 3 , Zeid A ALOthman 3 , Wagdy M Eldehna 4 , Radwan El-Haggar 5 , Robert McKenna 2 , Alessio Nocentini 1 , Claudiu T Supuran 1
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A new series of pyrimidine derivatives as human carbonic anhydrases (CA, EC 4.2.1.1) inhibitors is here designed by including a 5-fluorouracil (5-FU) moiety, broadly used anticancer medication, in nitrogenous base modulators of the tumor-associated CAs. Most sulfonamide derivatives efficiently inhibit the target CA IX (KIs in the range 0.47-44.7 nM) and CA XII (KIs in the range 2.9-83.1 nM), while the 5-FU coumarin derivatives showed a potent and totally selective inhibitory action against the target CA IX/XII over off-target CA I/II. The X-ray solved crystal structure of CA II in adduct with a representative uracil derivative provided insights on the binding mode to the target of such pyrimidine derivatives. On the basis of potency and selectivity inhibition profiles, coumarin 12a, the sulfonamide CAIs showing the greatest II/IX specificity (4e, 6b and 6d) and the unique subnanomolar CA IX inhibitor 10a were tested in vitro for their antiproliferative action against a panel of eight cancer cell lines. The breast cancer cell lines MDA-MB-231 and T47D were the most susceptible with IC50 values in low to medium micromolar ranges (2.45 ± 0.07-18.86 ± 0.72 μM and 6.86 ± 0.31-40.92 ± 1.59 μM, respectively). A cell cycle analysis showed that 4e and 6d arrest T-47D cells mainly in the G2/M phase. Using an annexin V-FITC apoptosis assay, 4e and 6d were shown to induce an approximately 23.6-fold and 34.8-fold total increase in apoptosis compared to the control, corroborating the concrete potential of 5-FU CAIs for the design of new effective anticancer strategies.
中文翻译：
将5-氟尿嘧啶部分包含在含氮碱基衍生物中作为人类碳酸酐酶IX和XII抑制剂可产生针对MDA-MB-231和T47D乳腺癌细胞的靶向作用。
本文设计了一系列新的嘧啶衍生物作为人类碳酸酐酶（CA，EC 4.2.1.1）抑制剂，方法是在肿瘤相关CA的含氮碱调节剂中加入5-氟尿嘧啶（5-FU）部分（广泛使用的抗癌药物） 。大多数磺酰胺衍生物可有效抑制目标CA IX（KI在0.47-44.7 nM范围内）和CA XII（KI在2.9-83.1 nM范围内），而5-FU香豆素衍生物则显示出对这种化合物有效的抑制作用。目标CA IX / XII而非目标CA I / II。X射线解析的具有代表性尿嘧啶衍生物的加合物中CA II的晶体结构提供了与此类嘧啶衍生物的靶标结合模式的见解。根据效价和选择性抑制曲线，香豆素12a，磺酰胺CAI表现出最大的II / IX特异性（4e，在体外测试了6b和6d）和独特的亚纳摩尔型CA IX抑制剂10a对一组八种癌细胞系的抗增殖作用。乳腺癌细胞系MDA-MB-231和T47D最易感，其IC50值处于中低微摩尔范围（分别为2.45±0.07-18.86±0.72μM和6.86±0.31-40.92±1.59μM）。细胞周期分析表明4e和6d将T-47D细胞主要阻滞在G2 / M期。使用膜联蛋白V-FITC凋亡测定法，与对照组相比，显示4e和6d诱导凋亡总数增加了约23.6倍和34.8倍，从而证实了5-FU CAI在设计新的有效抗癌药物方面的具体潜力策略。
更新日期：2020-02-03
中文翻译：
将5-氟尿嘧啶部分包含在含氮碱基衍生物中作为人类碳酸酐酶IX和XII抑制剂可产生针对MDA-MB-231和T47D乳腺癌细胞的靶向作用。
本文设计了一系列新的嘧啶衍生物作为人类碳酸酐酶（CA，EC 4.2.1.1）抑制剂，方法是在肿瘤相关CA的含氮碱调节剂中加入5-氟尿嘧啶（5-FU）部分（广泛使用的抗癌药物） 。大多数磺酰胺衍生物可有效抑制目标CA IX（KI在0.47-44.7 nM范围内）和CA XII（KI在2.9-83.1 nM范围内），而5-FU香豆素衍生物则显示出对这种化合物有效的抑制作用。目标CA IX / XII而非目标CA I / II。X射线解析的具有代表性尿嘧啶衍生物的加合物中CA II的晶体结构提供了与此类嘧啶衍生物的靶标结合模式的见解。根据效价和选择性抑制曲线，香豆素12a，磺酰胺CAI表现出最大的II / IX特异性（4e，在体外测试了6b和6d）和独特的亚纳摩尔型CA IX抑制剂10a对一组八种癌细胞系的抗增殖作用。乳腺癌细胞系MDA-MB-231和T47D最易感，其IC50值处于中低微摩尔范围（分别为2.45±0.07-18.86±0.72μM和6.86±0.31-40.92±1.59μM）。细胞周期分析表明4e和6d将T-47D细胞主要阻滞在G2 / M期。使用膜联蛋白V-FITC凋亡测定法，与对照组相比，显示4e和6d诱导凋亡总数增加了约23.6倍和34.8倍，从而证实了5-FU CAI在设计新的有效抗癌药物方面的具体潜力策略。
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