Department of Analytical, Environmental and Forensic Sciences, King's College London, London, UK.
Department of Drug and Health Sciences, University of Catania, Catania, Italy.
Bioorg Chem. 2021 Dec;117:105428. doi: 10.1016/j.bioorg.2021.105428. Epub 2021 Oct 20.
Up-regulation of HO-1 had been frequently reported in different cases and types of human malignancies. Since poor clinical outcomes are reported in these cases, this enzyme's inhibition is considered a valuable and proven anticancer approach. To identify novel HO-1 inhibitors suitable for drug development, we report a structure-guided fragment-based approach to identify new lead compounds. Different parts of the selected molecules were analyzed, and the different series of novel compounds were virtually evaluated. The growing experiments of the classical HO-1 inhibitors structure led us to different hit-compounds. A synthetic pathway for six selected molecules was designed, and the compounds were synthesized. The biological activity revealed that molecules 10 and 12 inhibit the HO-1 activity with an IC of 1.01 and 0.90 μM, respectively. This study suggested that our growing approach was successful, and these results are ongoing for further development.
HO-1 的上调在不同病例和类型的人类恶性肿瘤中经常被报道。由于这些病例报告的临床预后较差，因此抑制该酶被认为是一种有价值且经过验证的抗癌方法。为了鉴定适合药物开发的新型 HO-1 抑制剂，我们报告了一种基于结构的片段基方法来鉴定新的先导化合物。分析了所选分子的不同部分，并对不同系列的新型化合物进行了虚拟评估。对经典 HO-1 抑制剂结构的生长实验使我们得到了不同的命中化合物。设计了六个选定分子的合成途径，并合成了化合物。生物活性表明，化合物 10 和 12 以 1.01 和 0.90 μM 的 IC 抑制 HO-1 活性。本研究表明，我们的生长方法是成功的，这些结果正在进行进一步的开发。
