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Synthesis and anti-inflammatory activity of sulfonamides and carboxylates incorporating trimellitimides: Dual cyclooxygenase/carbonic anhydrase inhibitory actions.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-11-22 , DOI: 10.1016/j.bioorg.2018.11.033
Alaa A-M Abdel-Aziz 1 , Andrea Angeli 2 , Adel S El-Azab 3 , Mohammed E A Hammouda 4 , Magda A El-Sherbeny 5 , Claudiu T Supuran 2
Affiliation  

Trimellitimides 6-21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6-11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED50) of 34.3-49.8 mg kg-1 and 63.6-86.6% edema inhibition relative to the reference drug celecoxib (ED50: 33.9 mg kg-1 and 85.2% edema inhibition). Compounds 6-11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6-11 had optimal selectivity against COX-2. The selectivity index (SI) range was >200-490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12, 13, and 16-18 were nonselective COX inhibitors with a selectivity index range of 0.92-0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6-11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The KI ranges were 54.1-81.9 nM for hCA I, 25.9-55.1 nM for hCA II, and 46.0-348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved.

中文翻译:

结合有偏苯三甲酰亚胺的磺酰胺和羧酸盐的合成和抗炎活性:双重环氧合酶/碳酸酐酶的抑制作用。

制备了Trimellitimides 6-21,并在体内研究了抗炎和促溃疡作用,并在体外研究了细胞毒性。他们接受了体外环氧合酶(COX-1 / 2)和碳酸酐酶抑制方案。相对于参考药物塞来昔布(ED50:33.9 mg kg-1和85.2),化合物6-11和18表现出抗炎活性并具有34.3-49.8 mg kg-1的中位有效剂量(ED50)和63.6-86.6%的水肿抑制作用。水肿抑制百分比)。与参考标准5-氟尿嘧啶(5-FU)相比,化合物6-11和18在10μM时对59种细胞系的细胞毒性较弱。化合物6-11对COX-2具有最佳选择性。选择性指数(SI)范围> 200-490,与塞来昔布[COX-2(SI)> 416.7]相当。相反,化合物12、13 和16-18是非选择性COX抑制剂,选择性指数范围为0.92-0.25。碳酸酐酶抑制试验表明,磺胺结合了偏苯三甲酸酯6-11抑制了胞质亚型hCA I和hCA II,以及与肿瘤相关的亚型hCA IX。它们相对更容易受到化合物8、9和11的抑制。hCAI的KI范围为54.1-81.9 nM,hCA II的KI范围为25.9-55.1 nM,hCA IX的KI范围为46.0-348.3 nM。©2018爱思唯尔科学。版权所有。hCA II为1 nM,hCA IX为46.0-348.3 nM。©2018爱思唯尔科学。版权所有。hCA II为1 nM,hCA IX为46.0-348.3 nM。©2018爱思唯尔科学。版权所有。
更新日期:2018-11-22
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