Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt; Department of Biochemistry & Molecular Genetics, University of Colorado, Anschutz Medical Campus, Denver, USA.
Bioorg Med Chem. 2020 Jun 1;28(11):115495. doi: 10.1016/j.bmc.2020.115495. Epub 2020 Apr 11.
New series of benzimidazole ring core conjugated with either dithiocarbamate or thiopropyl linkers, hybridized with different secondary amines were synthesized; 5-15 and 22-31; respectively. The new compounds were characterized by different spectroscopic techniques (H, C 1D & 2D NMR, ESI-MS and IR). They were screened for in vitro anticancer activity against breast cancer using MCF7 cell line. The results obtained revealed that compounds 5, 12, 15 and 25 were the most active among the synthesized series exhibiting IC < 10 µg/ml against DOX. To characterize targeting breast cancer on molecular level, binding to N-labeled Pin1 enzyme was conducted using state-of-the-art 2D NMR binding experiments. Results showed promising binding between compounds 5, 12, and 25 by chemical shift perturbation (peak shifting or peak disappearance). Molecular docking study were quite valuable to explain the binding mode of active derivatives via hydrogen bonding. Additional contact preferences and surface mapping studies stated the similarity pattern between active candidates which may pave the way for more precise anti breast cancer target optimization.
新的苯并咪唑环核心系列化合物与二硫代氨基甲酸盐或硫代丙基连接体混合，分别与不同的仲胺杂交，得到化合物 5-15 和 22-31。这些新化合物通过不同的光谱技术（H、C 1D 和 2D NMR、ESI-MS 和 IR）进行了表征。它们被筛选出具有体外抗乳腺癌活性，使用 MCF7 细胞系进行了测试。结果表明，在合成的系列化合物中，化合物 5、12、15 和 25 是最活跃的，对 DOX 的 IC < 10μg/ml。为了在分子水平上表征针对乳腺癌的靶向性，使用最先进的 2D NMR 结合实验进行了与 N 标记的 Pin1 酶的结合。结果表明，化合物 5、12 和 25 之间存在有希望的结合，通过化学位移扰动（峰移动或峰消失）。分子对接研究对于通过氢键解释活性衍生物的结合模式非常有价值。附加的接触偏好和表面映射研究表明了活性候选物之间的相似模式，这可能为更精确的抗乳腺癌靶标优化铺平道路。
