Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Zagreb, Croatia.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):163-174. doi: 10.1080/14756366.2020.1850711.
Newly synthesised benzimidazole/benzotiazole derivatives bearing amidino, namely 3,4,5,6-tetrahydropyrimidin-1-ium chloride, substituents have been evaluated for their potential antitumor activity . Compounds and standard drugs (doxorubicin, staurosporine and vandetanib) were tested on three human lung cancer cell lines A549, HCC827 and NCI-H358. We tested compounds in MTS citotoxicity assay and in BrdU proliferative assay performed on 2 D and 3 D assay format. Because benzmidazole scaffold is similar to natural purines, we tested the most active compounds for ability to induce cell apoptosis of A549 by binding to DNA in comparison with doxorubicin and saturosporine. Additionally, the ADME properties of the most active benzothiazole/benzimidazole and non-active compounds were determined to see if the different ADME properties are the cause of different activity in 2 D and 3 D assays, as well as to see if the tested active compounds have drug like properties and potency for further profilation. ADME characterisation included solubility, lipophilicity, permeability, metabolic stability and binding to plasma proteins. In general, the benzothiazole derivatives were more active in comparison to their benzimidazole analogues. The exception was 2-phenyl substituted benzimidazole being active with very pronounced activity especially towards HCC827 cells. All active compounds have similar mode of action on A549 cell line as standard compound doxorubicin, which binds to nucleic acids with the DNA double helix. Tested active benzothiazole compounds were characterised by moderate to good solubility, good metabolic stability, low permeability and high binding to plasma proteins. One tested active benzimidazole derivative showed ADME properties, but lower lipophilicity resulted in low PPB and higher metabolic instability. In addition, no significant difference was observed in ADME profile between active and non-active compounds.
新合成的苯并咪唑/苯并噻唑衍生物带有脒基，即 3,4,5,6-四氢嘧啶-1-鎓氯化物取代基，已评估其潜在的抗肿瘤活性。将化合物和标准药物（阿霉素、司他唑啉和凡德他尼）在三种人肺癌细胞系 A549、HCC827 和 NCI-H358 上进行了测试。我们在 2D 和 3D 测定中使用 MTS 细胞毒性测定和 BrdU 增殖测定测试了化合物。因为苯并咪唑支架类似于天然嘌呤，所以我们测试了最活跃的化合物，比较阿霉素和司他唑啉，观察它们与 DNA 结合诱导 A549 细胞凋亡的能力。此外，还测定了最活跃的苯并噻唑/苯并咪唑和非活性化合物的 ADME 特性，以确定不同的 ADME 特性是否是 2D 和 3D 测定中不同活性的原因，以及测试的活性化合物是否具有类药性和进一步分析的潜力。ADME 特征包括溶解度、脂溶性、渗透性、代谢稳定性和与血浆蛋白的结合。一般来说，与苯并咪唑类似物相比，苯并噻唑衍生物更具活性。例外的是 2-苯基取代的苯并咪唑 ，对 HCC827 细胞表现出非常显著的活性。所有活性化合物对 A549 细胞系的作用方式与标准化合物阿霉素相似，阿霉素与 DNA 双螺旋结合。测试的活性苯并噻唑化合物具有中等至良好的溶解度、良好的代谢稳定性、低渗透性和高与血浆蛋白的结合。一种测试的活性苯并咪唑衍生物具有 ADME 特性，但较低的脂溶性导致较低的 PPB 和较高的代谢不稳定性。此外，活性和非活性化合物之间在 ADME 特征上没有观察到显著差异。
