New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling.
New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling.
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DOI：
10.3390/ph15091134
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发表时间：
2022-09-10
期刊：
影响因子：
--
通讯作者：
Elshemy HAH
中科院分区：
文献类型：
--
作者：
Abdelgawad MA;Bukhari SNA;Musa A;Elmowafy M;Elkomy MH;Nayl AA;El-Ghorab AH;Alsohaimi IH;Abdel-Bakky MS;Althobaiti IO;Altaleb HA;Omar HA;Abdelazeem AH;Zaki MA;Shaker ME;Elshemy HAH
在这项研究中，新的磺胺甲恶唑衍生物（S1-S4，S6-S12，和S14-S22）的设计和合成，其结构进行了充分的表征和验证，使用NMR，质谱，红外光谱，以及元素分析。测定所有新衍生物（S1-S22）对人碳酸酐酶（hCA IX和XII）的抑制活性。选择hCA IX和XII是因为CAIX表达被认为是乳腺癌中预后不良的缺氧标志物。与盐酸多佐胺作为标准参比品相比，衍生物S2、S3、S8、S9和S15具有最有效的抑制作用，IC 50值较低。进一步评价活性化合物对hCA I和II的抑制活性，与参比标准品乙酰唑胺相比，化合物S8、S9和S15显示出最小的抑制作用，表明它们在正常细胞中的作用最低。对MCF 7（常氧和缺氧）和正常乳腺细胞系（MCF 10a）进行所选化合物的细胞活力测试，星形孢菌素作为标准。结果表明，化合物S15具有很强的细胞毒作用。此外，细胞周期分析结果显示化合物S15触发MCF 7癌细胞的细胞周期停滞和G1/S期的凋亡。最后，进行分子对接，以指出我们的配体与hCAs IX和XII的重要结构特征和关键相互作用的可能解释，这些配体可能共享额外的设计，并突出显示有希望的抗癌剂的可能线索。因此，磺胺甲恶唑衍生物S15可能是新兴的选择性细胞毒性化合物定向h CA IX和XII的潜在先导物。
In this study new sulphamethoxazole derivatives (S1–S4, S6–S12, and S14–S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. All new derivatives (S1–S22) were assayed against human carbonic anhydrase (hCAs IX and XII) for their inhibitory activities. hCAs IX and XII were chosen due to the fact that CAIX expression is recognized as a hypoxia marker with a poor prognosis in breast cancer. When compared to Dorzolamide HCl as a standard reference, derivatives S2, S3, S8, S9, and S15 had the most effective inhibition with low IC50 values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds S8, S9 and S15 showed the least inhibitory effect compared to the reference standard, acetazolamide, indicating that their effect in normal cells is the lowest. Cell viability tests for the selected compounds were carried out on MCF7 (normoxia and hypoxia) and on the normal breast cell line (MCF10a) with Staurosporine as a standard. The results showed that compound S15 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound S15 triggered cell cycle arrest and apoptosis in G1/S of MCF7 cancer cells. Finally, molecular docking was performed to point out the possible explanation for the vital structural features and key-interactions exerted by our ligands with hCAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative S15 could be the potential lead for emerging selective cytotoxic compounds directing h CAs IX and XII.
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影响因子：
5.1
作者：
Eldehna, Wagdy M.;Abo-Ashour, Mahmoud F.;Supuran, Claudiu T.
通讯作者：
Supuran, Claudiu T.
影响因子：
5.1
作者：
Akocak, Suleyman;Lolak, Nabih;Supuran, Claudiu T.
通讯作者：
Supuran, Claudiu T.
影响因子：
2.7
作者：
Parkkila, Seppo;Innocenti, Alessio;Supuran, Claudiu T.
通讯作者：
Supuran, Claudiu T.
DOI：
10.5012/jkcs.2018.62.5.377
发表时间：
2018-10-20
影响因子：
0.5
作者：
Khanusiya, Mahammadali;Gadhawala, Zakirhusen
通讯作者：
Gadhawala, Zakirhusen
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.