Kececi Sarıkaya Meryem, Sahin Yaglioglu Ayse, Ceylan Mustafa, Yırtıcı Ümit
Tokat Gaziosmanpaşa University, Department of Chemistry, 60250, Tokat, Türkiye.
Amasya University, Technical Sciences Vocational School, Department of Chemistry and Chemical Process Technology, 05186, Amasya, Türkiye.
Chem Biodivers. 2025 Feb;22(2):e202401980. doi: 10.1002/cbdv.202401980. Epub 2024 Nov 16.
The target benzothiazole derivatives (8a-g) were synthesized starting from norbornene. The addition of dichloroketene to norbornene followed by the reduction of chlorine atoms were synthesized tricyclo[4.2.1.02,5]non-7-en-3-one (4). The condensation of benzaldehyde derivatives with compound 4 were obtained chalcone analogs (6a-g). Finally, benzothiazole derivatives (8a-g) were obtained by the reaction of the chalcone analogs with 2-aminobenzothiol in an acidic medium. The antiproliferative activities of compounds 6a-g and 8a-g were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma) cell lines using a BrdU cell proliferation ELISA assay with 5-fluorouracil (5-FU) as a standard. In both series, when compared with 5-FU (IC=3.8 μM for C6 and 16.33 μM for HeLa), the most active compounds against C6 cells were 6a and 8g with IC values of 14.13 μM and 29.99 μM, respectively. With this, 6a, 6e, 6f, and 8b were the most active compounds against HeLa cells with IC values of 0.8, 1.21, 19.33 and 18.13 μM, respectively. Additionally, the SwissADME online web tool was used to predict the physicochemical and ADME properties of the tested compounds. The results showed that all compounds possess promising predicted physiochemical and pharmacokinetic properties and comply with Lipinski's rule of 5, indicating that they are predicted to be orally bioavailable that they possess a predicted bioavailability score of 0.55. Furthermore, in the SwissADME Boiled-Egg chart, all compounds showed high predicted GIT absorption, while compounds 6a-g showed blood-brain barrier (BBB) permeation, and compounds 8a-g did not. Moreover, none of the compounds was (P-gp) substrates. This study investigated the potential interactions between the antiapoptotic proteins Bcl-2, Bcl-xl, Bcl-w, Brag-1, Bfl-1, and Mcl-1 and compounds 6a, 8b, and 8g through molecular docking studies. The findings suggest that these compounds may effectively inhibit antiapoptotic proteins, as evidenced by significant hydrogen bonds and hydrophobic interactions, particularly with Bcl-xl.
目标苯并噻唑衍生物（8a - g）以降冰片烯为起始原料合成。降冰片烯与二氯烯酮加成，随后氯原子还原，合成了三环[4.2.1.02,5]壬 - 7 - 烯 - 3 - 酮（4）。苯甲醛衍生物与化合物4缩合得到查尔酮类似物（6a - g）。最后，查尔酮类似物与2 - 氨基苯硫酚在酸性介质中反应得到苯并噻唑衍生物（8a - g）。使用以5 - 氟尿嘧啶（5 - FU）为标准的BrdU细胞增殖ELISA测定法，测定了化合物6a - g和8a - g对C6（大鼠脑肿瘤）和HeLa（人宫颈癌）细胞系的抗增殖活性。在这两个系列中，与5 - FU（对C6细胞的IC = 3.8 μM，对HeLa细胞的IC = 16.33 μM）相比，对C6细胞活性最高的化合物是6a和8g，IC值分别为14.13 μM和29.99 μM。由此，6a、6e、6f和8b是对HeLa细胞活性最高的化合物，IC值分别为0.8、1.21、19.33和18.13 μM。此外，使用SwissADME在线网络工具预测测试化合物的物理化学和ADME性质。结果表明，所有化合物都具有良好的预测物理化学和药代动力学性质，符合Lipinski的五规则，表明它们预计具有口服生物利用度，其预测生物利用度评分为0.55。此外，在SwissADME煮鸡蛋图中，所有化合物都显示出较高的预测胃肠道吸收，而化合物6a - g显示出血脑屏障（BBB）通透性，化合物8a - g则没有。而且，没有一种化合物是（P - gp）底物。本研究通过分子对接研究调查了抗凋亡蛋白Bcl - 2、Bcl - xl、Bcl - w、Brag - 1、Bfl - 1和Mcl - 1与化合物6a、8b和8g之间的潜在相互作用。研究结果表明，这些化合物可能有效抑制抗凋亡蛋白，显著的氢键和疏水相互作用证明了这一点，特别是与Bcl - xl的相互作用。
