Elgohary Mohamed K, Elkotamy Mahmoud S, Al-Warhi Tarfah, Eldehna Wagdy M, Abdel-Aziz Hatem A
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt.
Bioorg Chem. 2024 Dec;153:107766. doi: 10.1016/j.bioorg.2024.107766. Epub 2024 Aug 28.
LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC = 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC = 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein-protein interaction, where they displayed IC values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22- and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.
LSM - 83177是一种苯氧基乙酸衍生物，是一种据报道具有良好抗肿瘤特性的小分子。通过抑制MDM2与p53之间的相互作用，LSM - 83177可以提高细胞内活性p53水平，从而促进细胞凋亡并抑制肿瘤生长。此外，LSM - 83177已被证明可抑制结直肠癌HT29细胞中的GST活性。在当前工作中，根据LSM - 83177的结构特征及其在MDM2活性位点的结合模式，设计了新型LSM - 83177腙类似物5a - f、7a - b、10a - e和13a - b。评估了新合成类似物对HT29细胞系的抗癌活性。与作为参考药物的顺铂（IC = 11.32 µg/ml）相比，最有效的化合物7a和10a的IC值分别为12.48和10.44 µg/ml。引入化合物7a和10a进一步检测p53 - MDM2蛋白 - 蛋白相互作用，其IC值分别为3.65和11.08 µg/ml。此外，腙7a和10a分别使p - 53表达水平提高了3.22倍和4.25倍；此外，与未处理的对照相比，它们有效降低了HT29癌细胞中的GST表达水平，增量分别为0.56倍和0.30倍。
