Aboukhatwa Shaimaa M, Sidhom Peter A, Angeli Andrea, Supuran Claudiu T, Tawfik Haytham O
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
ACS Omega. 2023 Feb 17;8(8):7666-7683. doi: 10.1021/acsomega.2c07285. eCollection 2023 Feb 28.
With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub- to two-digit micromolar potency (GI down to 0.3 μM and LC as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity with being the most potent, having an average Ki value of 4 μM. Compound showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms . Cytotoxicity of both and in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in treated colorectal carcinoma, HCT116, cells compared to the control. Compound arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both and showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents and being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics.
秉持“少即是多”的理念，设计了一系列15种查尔酮 - 磺酰胺杂化物，期望具有协同抗癌活性。芳香磺酰胺部分因其锌螯合特性作为已知的碳酸酐酶IX活性直接抑制剂被纳入。查尔酮部分作为亲电应激源被引入，以间接抑制碳酸酐酶IX的细胞活性。美国国立癌症研究所（NCI）的发展治疗项目NCI - 60筛选显示，12种衍生物是多种细胞系中癌细胞生长的有效抑制剂，并进入五剂量筛选。癌细胞生长抑制谱表明，特别是对结肠癌细胞具有亚微摩尔至两位数微摩尔的效力（GI低至0.3μM，LC低至4μM）。出乎意料的是，大多数化合物作为碳酸酐酶催化活性的直接抑制剂表现出低至中等的效力，其中 最有效，平均Ki值为4μM。化合物 对碳酸酐酶IX的选择性比其他测试同工型高约六倍。 和 在缺氧条件下对活的HCT116、U251和LOX IMVI细胞的细胞毒性证实了它们对碳酸酐酶活性的靶向作用。与对照相比，处理后的结肠癌细胞HCT116中Nrf2和ROS水平的增加表明细胞氧化应激升高。化合物 使HCT116细胞的细胞周期停滞在G1/S期。此外，与非癌性HEK293T细胞相比， 和 均表现出高达50倍的癌细胞选择性。因此，本研究提出 和 是新的、可通过合成获得的、设计简单的衍生物，作为有潜力进一步开发为抗癌治疗药物的候选物。
