Arylidine extensions of 3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-benzenesulfonamide derivatives：合成、计算模拟和生物评估作为肿瘤相关的碳酸酐酶抑制剂。
Arylidine extensions of 3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-benzenesulfonamide derivatives: Synthesis, computational simulations and biological evaluation as tumor-associated carbonic anhydrase inhibitors.
发表日期：2023 Mar 24
作者：
Heba M Metwally, Heba Abdelrasheed Allam, Fady Baselious, Alessandro Bonardi, Emad M Seif, Shaimaa A Moussa, Ehab Abdel-Latif, Claudiu T Supuran, Hany S Ibrahim
来源：
BIOORGANIC CHEMISTRY
摘要：
几种吡唑苯磺酰胺被报道为人类碳酸酐酶抑制剂。在这项研究工作中，基于尾端法设计，报道了Arylidine-extended 5-oxo-pyrazole benzenesulfonamides (4a-i)，(8a-d)和(10a-e)的设计。除了报道的合成程序和不同分析程序的确认外，还采用DFT研究确认了合成化合物的Z构型。进行了体外生物活性测定，针对四种不同的人类碳酸酐酶，并根据结果进行SAR研究和选择性指数的讨论。化合物4g和8a在目标化合物中表现出最佳的抑制活性，值为(hCAIX: KI=71.2 nM，hCAXII:KI=22.5 nM)，(hCAIX: KI=34.3 nM，hCAXII: KI=74.3 nM);分别。两者都被用于细胞测定，针对两种表达hCA亚型的不同癌细胞系，在正常氧和低氧条件下进行。化合物4g对MCF-7癌细胞系的细胞毒性活性最高（在低氧情况下IC50=4.15µM，在正常氧情况下，IC50=8.59µM），与参考药物多柔比星相比，在正常氧（IC50=4.34µM）和低氧（IC50=2.23µM）条件下。进一步的细胞研究被用于研究这种化合物对受影响的细胞系的细胞周期的影响。最后，利用分子对接与分子动力学模拟来理解所设计的两个化合物的抑制活性机制-Copyright © 2023 Elsevier Inc. All rights reserved。
Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: KI = 71.2 nM, hCAXII: KI = 22.5 nM), (hCAIX: KI = 34.3 nM, hCAXII: KI = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC50 = 4.15 µM under hypoxic conditions and IC50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC50 = 4.34 µM), and hypoxic, (IC50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds - as representative examples- based on the designed rational.Copyright © 2023 Elsevier Inc. All rights reserved.