Laboratory for Molecular and Cellular Biology, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička Cesta 54, HR-10000 Zagreb, Croatia.
Molecules. 2012 Jun 28;17(7):7864-86. doi: 10.3390/molecules17077864.
In vitro high-throughput screening was carried out in order to detect new activities for old drugs and to select compounds for the drug development process comprising new indications. Tebrophen, a known antiviral drug, was found to inhibit activities on inflammation and cancer related targets. In primary screening this semisynthetic halogenated polyphenol was identified to inhibit the activities of kinases ZAP-70 and Lck (IC₅₀ 0.34 µM and 16 µM, respectively), as well as hydrolase DPPIV (at 80 µM 41% inhibition). Next, it showed no cytotoxic effects on standard cell lines within 24 h. However, tebrophen slowed propagation of breast cancer (MDA-MB-231), osteosarcoma (U2OS) and cervical carcinoma (HeLa), through at least 35 population doublings in a dose-dependent manner. It completely stopped the division of the prostate cancer (PC3) cell line at 50 µM concentration and the cells entered massive cell death in less than 20 days. On the other hand, tebrophen did not influence the growth of normal fibroblasts. According to the measured oxidative burst and estimated in silico parameters its direct antioxidative ability is limited. The obtained results indicate that tebrophen can be considered a promising lead molecule for generating more soluble derivatives with specific anticancer efficacy.
为了检测旧药物的新活性并选择化合物用于包含新适应症的药物开发过程，进行了体外高通量筛选。发现 Tebrophen（一种已知的抗病毒药物）能够抑制炎症和癌症相关靶点的活性。在初步筛选中，这种半合成卤代多酚被鉴定为抑制激酶 ZAP-70 和 Lck 的活性（IC₅₀ 分别为 0.34 µM 和 16 µM），以及水解酶 DPPIV（在 80 µM 时抑制 41%）。接下来，它在 24 小时内对标准细胞系没有细胞毒性作用。然而，Tebrophen 通过至少 35 个倍增的剂量依赖性方式减缓了乳腺癌（MDA-MB-231）、骨肉瘤（U2OS）和宫颈癌（HeLa）的增殖。它在 50 µM 浓度下完全阻止了前列腺癌（PC3）细胞系的分裂，并且细胞在不到 20 天的时间内大量死亡。另一方面， Tebrophen 不会影响正常成纤维细胞的生长。根据测量的氧化爆发和估计的计算参数，其直接抗氧化能力是有限的。所得结果表明，Tebrophen 可以被认为是生成具有特定抗癌功效的更可溶性衍生物的有前途的先导分子。
