Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria, Egypt.
Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Bioorg Chem. 2021 Aug;113:105033. doi: 10.1016/j.bioorg.2021.105033. Epub 2021 May 27.
STAT3 signaling is known to be associated with tumorigenesis and further cancer cell-intrinsic activation of STAT3 leads to altered regulation of several oncogenic processes. Given the importance of STAT3 in cancer development and progression particularly breast cancer, it is crucial to discover new chemical entities of STAT3 inhibitor to develop anti-breast cancer drug candidates. Herein, 4-benzyl-2-benzylthio-5-methyl-1H-imidazole (2a) and 4-benzyl-5-methyl-2-[(2,6-difluorobenzyl)thio]-1H-imidazole (2d) from a group of thirty imidazole-bearing compounds showed greater STAT3 inhibition than their lead compounds VS1 and the oxadiazole derivative MD77. Within all tested compounds, ten derivatives effectively inhibited the growth of the two tested breast cancer cells with IC values ranging from 6.66 to 26.02 µM. In addition, the most potent derivatives 2a and 2d inhibited the oncogenic function of STAT3 as seen in the inhibition of colony formation and IL-6 production of breast cancer cell lines. Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the STAT3-SH2 domain. Collectively, our present study suggests 2-substituted-4-benzyl-5-methylimidazoles are a new class of anti-cancer drug candidates to inhibit oncogenic STAT3 function.
STAT3 信号通路与肿瘤发生有关，进一步激活 STAT3 会导致几个致癌过程的调节发生改变。鉴于 STAT3 在癌症发展和进展中的重要性，特别是在乳腺癌中，发现新的 STAT3 抑制剂化学实体对于开发抗乳腺癌药物候选物至关重要。在此，从三十种含咪唑的化合物中，4-苄基-2-苄基硫代-5-甲基-1H-咪唑（2a）和 4-苄基-5-甲基-2-[(2,6-二氟苄基)硫代]-1H-咪唑（2d）比其先导化合物 VS1 和噁二唑衍生物 MD77 对 STAT3 的抑制作用更强。在所测试的所有化合物中，有十个衍生物能够有效抑制两种测试的乳腺癌细胞的生长，IC 值范围为 6.66 至 26.02µM。此外，最有效的衍生物 2a 和 2d 抑制了乳腺癌细胞系中 STAT3 的致癌功能，如集落形成和 IL-6 产生的抑制。建模研究为合成化合物与 STAT3-SH2 结构域关键残基的可能相互作用提供了证据。总的来说，我们目前的研究表明，2-取代-4-苄基-5-甲基咪唑是一类新的抗癌药物候选物，可以抑制致癌 STAT3 功能。
