Abdelgawad Mohamed A, Bukhari Syed N A, Musa Arafa, Elmowafy Mohammed, Elkomy Mohammed H, Nayl AbdElAziz A, El-Ghorab Ahmed H, Alsohaimi Ibrahim Hotan, Abdel-Bakky Mohamed Sadek, Althobaiti Ibrahim O, Altaleb Hamud A, Omar Hany A, Abdelazeem Ahmed H, Zaki Mohamed A, Shaker Mohamed E, Elshemy Heba A H
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72431, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
Pharmaceuticals (Basel). 2022 Sep 10;15(9):1134. doi: 10.3390/ph15091134.
In this study new sulphamethoxazole derivatives (, , and ) 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 () 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 , , , , and had the most effective inhibition with low IC values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds , and 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 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound 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 CAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative could be the potential lead for emerging selective cytotoxic compounds directing CAs IX and XII.
在本研究中，设计并合成了新型磺胺甲恶唑衍生物（、和），并使用核磁共振、质谱、红外光谱以及元素分析对其结构进行了全面表征和验证。对所有新型衍生物（）针对人碳酸酐酶（hCAs IX和XII）进行了抑制活性测定。选择hCAs IX和XII是因为CAIX表达被认为是乳腺癌预后不良的缺氧标志物。与作为标准对照的盐酸多佐胺相比，衍生物、、、、和具有最低IC值的最有效抑制作用。对活性化合物进一步评估了其对hCAs I和II的抑制活性，与参考标准乙酰唑胺相比，化合物、和显示出最低的抑制作用，表明它们在正常细胞中的作用最低。以星形孢菌素为标准，对所选化合物在MCF7（常氧和缺氧）和正常乳腺细胞系（MCF10a）上进行了细胞活力测试。结果表明化合物具有高效的细胞毒性作用。此外，细胞周期分析结果表明化合物在MCF7癌细胞的G1/S期引发细胞周期阻滞和凋亡。最后，进行了分子对接，以指出我们的配体与CAs IX和XII之间重要结构特征和关键相互作用的可能解释，这可能有助于进一步设计并突出有望成为抗癌药物的潜在先导物。因此，磺胺甲恶唑衍生物可能是针对CAs IX和XII的新型选择性细胞毒性化合物的潜在先导物。
