作为有效和选择性 c-MYC 转录抑制剂的苯并硒唑衍生物的开发和表征,Journal of Medicinal Chemistry

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作为有效和选择性 c-MYC 转录抑制剂的苯并硒唑衍生物的开发和表征
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-04-10 , DOI: 10.1021/acs.jmedchem.2c01808
Tian-Ying Wu ₁ , Xiu-Cai Chen ₁ , Gui-Xue Tang ₁ , Wen Shao ₁ , Zhang-Chi Li ₁ , Shuo-Bin Chen ₁ , Zhi-Shu Huang ₁ , Jia-Heng Tan ₁

Affiliation

开发针对 G-四链体的c-MYC转录抑制剂引起了人们的极大兴趣；然而，很少有化合物表现出对c-MYC G-四链体和癌细胞的特异性。在这项研究中，我们设计并合成了一系列苯并唑衍生物作为潜在的基于 G-四联体配体的c-MYC转录抑制剂。令人惊讶的是，与苯并噻唑和苯并恶唑类似物相比，很少作为 G-四链体配体报道的苯并硒唑衍生物表现出更高的c-MYC G-四链体选择性和癌细胞特异性。最有前途的化合物苯并硒唑m-Se3选择性抑制c-MYC通过特异性稳定c-MYC G-四链体进行转录。这导致通过影响 MYC 靶基因网络选择性抑制肝癌细胞生长和增殖，以及在肝癌细胞异种移植物中有效抑制肿瘤生长。总的来说，我们的研究表明，m-Se3作为一种有效的选择性c-MYC转录抑制剂在癌症治疗中具有重要的前景。此外，我们的发现激发了新型含硒杂环化合物作为c-MYC G-四链体特异性配体和转录抑制剂的开发。

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Development and Characterization of Benzoselenazole Derivatives as Potent and Selective c-MYC Transcription Inhibitors

Developing c-MYC transcription inhibitors that target the G-quadruplex has generated significant interest; however, few compounds have demonstrated specificity for c-MYC G-quadruplex and cancer cells. In this study, we designed and synthesized a series of benzoazole derivatives as potential G-quadruplex ligand-based c-MYC transcription inhibitors. Surprisingly, benzoselenazole derivatives, which are rarely reported as G-quadruplex ligands, demonstrated greater c-MYC G-quadruplex selectivity and cancer cell specificity compared to their benzothiazole and benzoxazole analogues. The most promising compound, benzoselenazole m-Se3, selectively inhibited c-MYC transcription by specifically stabilizing the c-MYC G-quadruplex. This led to selective inhibition of hepatoma cell growth and proliferation by affecting the MYC target gene network, as well as effective tumor growth inhibition in hepatoma xenografts. Collectively, our study demonstrates that m-Se3 holds significant promise as a potent and selective inhibitor of c-MYC transcription for cancer treatment. Furthermore, our findings inspire the development of novel selenium-containing heterocyclic compounds as c-MYC G-quadruplex-specific ligands and transcription inhibitors.

更新日期：2023-04-10

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