Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, 11942 Al Kharj, Saudi Arabia.
University Central Laboratory, College of Science and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, 11942 Al Kharj, Saudi Arabia.
Molecules. 2019 Mar 8;24(5):963. doi: 10.3390/molecules24050963.
β-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of β-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (⁻) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against β-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and β-glucuronidase, , , and compounds were docked into the active binding site of β-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and β-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-β-glucuronidase complexes.
β-葡糖苷酸酶是一种溶酶体糖苷酶，可催化肿瘤和正常细胞的细胞外基质以及细胞膜的糖胺聚糖，这对于癌细胞的增殖、侵袭和转移非常重要。肝癌、结肠癌和膀胱癌的发生是由于β-葡糖苷酸酶活性水平的增加。由于其药理作用，吲哚和恶二唑是最有价值的结构，因为其具有多种生物学特性而备受关注。合成了 22 种（⁻）基于吲哚的恶二唑类似物，并对其抑制β-葡糖苷酸酶的潜力进行了筛选。大多数化合物表现出很强的抑制潜力，IC 值在 0.9 ± 0.01 至 46.4 ± 0.9 µM 之间，阳性对照标准药物 D-葡萄糖酸 1,4-内酯（IC = 48.1 ± 1.2 µM）。对所有合成化合物都建立了结构活性关系（SAR）。为了阐明合成化合物与β-葡糖苷酸酶之间的分子相互作用，对 、 、 和 化合物进行了对接，以进入β-葡糖苷酸酶的活性结合位点。结果表明，这种结合在热力学上是有利的，所选化合物与β-葡糖苷酸酶复合物中氢键的建立数量增加，所选化合物对β-葡糖苷酸酶的抑制作用也随之增加。
