Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt.
Bioorg Chem. 2020 May;98:103752. doi: 10.1016/j.bioorg.2020.103752. Epub 2020 Mar 12.
Two new series of hybrid structures 16a-f and 19a-f containing 1,2,4-triazole moiety, pyrazole core with COX-2 pharmacophore and oxime as NO donor moiety were designed, synthesized and evaluated for anti-inflammatory, cytotoxic activities and NO release. All compounds were more selective for COX-2 isozyme especially the sulphamoyl derivatives (16b, 16e, 19b and 19e) had COX-2 selectivity indexes (S.I. = 9.78, 8.57, 10.78 and 10.47 respectively) in comparison to celecoxib (S.I. = 8.68). Similarly, 16b, 16e, 19b and 19e were the most potent anti-inflammatory derivatives with ED = 46.98-54.45 μmol/kg better than celecoxib (ED = 76.09 μmol/kg). Also, 16b, 16e, 19b and 19e were significantly less ulcerogenic (ulcer indexes = 2.79-3.95) upon comparison with ibuprofen (ulcer index = 20.25) and comparable with celecoxib (ulcer index = 2.93). Regarding anti-cancer activity, most of the target derivatives 16a-f and 19a-f showed good activities against A-549, MCF-7, HCT-116 and PC-3 cancer cell lines. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The sulphamoyl derivatives with internal oxime 19b and 19e were the most potent derivatives against all used cell lines especially PC-3 (IC50 = 1.48 and 0.33 µM respectively) with 11.75 and 39.4-fold respectively selectivity towards PC-3 than F180 fibroblasts. The mechanistic investigation of 19b and 19e revealed that both compounds arrested cell cycle at G2/M phase by 32.16 and 39.95 folds, up-regulated Bax expression by 6.83 and 14.52 folds and down-regulated the expression of the gene Bcl-2 by 0.57 and 0.36fold respectively. Also, 19b and 19e were good inhibitor for p38MAPK (0.65 for 19b and 0.58 for 19e) and VEGFR-2 (0.39 for 19b and 0.54 for 19e) in comparison with PC-3 control cell. All compounds 16a-f and 19a-f released NO in a slow rate (0.15-3.17%) and the four sulphamoyl derivatives 16b, 16e, 19b and 19e were the most NO releasers (3.06, 2.15, 3.17 and 2.54% respectively). Docking studies were carried out to explain the interaction of 16a-f and 19a-f with the target enzymes. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding EGFR inhibition, docking was carried out with ID: 1M17. The internal oxime serious was more active as anticancer because of their ability to form extra HBs with receptor cleft.
两种新的杂合结构 16a-f 和 19a-f 被设计、合成并评估了其抗炎、细胞毒性活性和一氧化氮释放，它们含有 1,2,4-三唑部分、吡唑核心和 COX-2 药效团以及肟作为 NO 供体部分。所有化合物对 COX-2 同工酶更具选择性，特别是磺酰胺衍生物（16b、16e、19b 和 19e）与塞来昔布（COX-2 选择性指数（S.I.）分别为 9.78、8.57、10.78 和 10.47）相比具有更高的 COX-2 选择性指数（S.I.）。同样，16b、16e、19b 和 19e 是最有效的抗炎衍生物，ED50 为 46.98-54.45 μmol/kg，优于塞来昔布（ED50 为 76.09 μmol/kg）。此外，16b、16e、19b 和 19e 的溃疡指数（溃疡指数分别为 2.79-3.95）明显低于布洛芬（溃疡指数为 20.25），与塞来昔布（溃疡指数为 2.93）相当。关于抗癌活性，大多数目标衍生物 16a-f 和 19a-f 对 A-549、MCF-7、HCT-116 和 PC-3 癌细胞系表现出良好的活性。此外，这些衍生物还针对 F180 成纤维细胞进行了测试，以研究它们的选择性指数。具有内部肟的磺酰胺衍生物 19b 和 19e 是对所有使用的细胞系最有效的衍生物，特别是对 PC-3（IC50 分别为 1.48 和 0.33 μM），对 PC-3 的选择性分别为 11.75 倍和 39.4 倍，对 F180 成纤维细胞的选择性分别为 39.95 倍。19b 和 19e 的机制研究表明，这两种化合物通过 32.16 倍和 39.95 倍使细胞周期停滞在 G2/M 期，通过 6.83 倍和 14.52 倍上调 Bax 表达，通过 0.57 倍和 0.36 倍下调 Bcl-2 基因的表达。此外，与 PC-3 对照细胞相比，19b 和 19e 对 p38MAPK（19b 为 0.65，19e 为 0.58）和 VEGFR-2（19b 为 0.39，19e 为 0.54）具有良好的抑制作用。所有化合物 16a-f 和 19a-f 以缓慢的速度（0.15-3.17%）释放一氧化氮，并且四个磺酰胺衍生物 16b、16e、19b 和 19e 是最有效的一氧化氮释放剂（分别为 3.06、2.15、3.17 和 2.54%）。进行了对接研究以解释 16a-f 和 19a-f 与靶酶的相互作用。最终设计化合物与塞来昔布（ID：3LN1）的对接模式表明，它们的三唑环采用 Y 形结构中的核心芳基。关于 EGFR 抑制，与 ID：1M17 进行了对接。内部肟基由于其与受体裂隙形成额外 HBs 的能力，因此更具抗癌活性。
