作为MARK4的强抑制剂的小分子Arylaldoxime / 5-Nitroimidazole杂种的设计和开发：一种基于靶点的癌症治疗的有前途的方法。,ACS Omega

当前位置： X-MOL 学术 › ACS Omega › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

作为MARK4的强抑制剂的小分子Arylaldoxime / 5-Nitroimidazole杂种的设计和开发：一种基于靶点的癌症治疗的有前途的方法。
ACS Omega ( IF 3.7 ) Pub Date : 2020-08-31 , DOI: 10.1021/acsomega.0c01703
Mudasir Nabi Peerzada ₁ , Parvez Khan ₂ , Nashrah Sharif Khan _{2,

3} , Fernando Avecilla ₄ , Shadab Miyan Siddiqui ₁ , Md Imtaiyaz Hassan ₂ , Amir Azam ₁

Affiliation

丝氨酸/苏氨酸激酶家族成员之一的微管亲和力调节激酶4（MARK4），由于参与微管动力学调节，细胞周期调节和癌症进展，是抗癌药物发现范例中的新兴治疗靶标。因此，为了鉴定出设计和开发具有伴随自由基清除性能的新型MARK4抑制剂的新颖化学结构，按照药效杂交方法，通过多步化学反应设计并合成了一系列小分子芳基醛肟/ 5-硝基咪唑共轭物。与筛选出的30种化合物相比，化合物4h被鉴定为对MARK4抑制具有高选择性的有前途的MARK4抑制剂与丝氨酸/苏氨酸家族有关的激酶已通过分子对接和荧光结合研究得到验证。全面的基于细胞的检查揭示了化学型4h有希望的凋亡，抗增殖和抗氧化潜能。化合物4小时被赋予与ķ_一个的3.6×10值³中号^-1对人血清白蛋白，这反映了其显着的运输和传送属性，以通过血液中的靶部位。本研究阻止在未来，此类化合物可作为通过MARK4抑制以显着的抗癌特性靶向癌症的药物发现中的最佳药理领先候选者。

"点击查看英文标题和摘要"

Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy.

Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h. The compound 4h was endowed with the K_a value of 3.6 × 10³ M^–1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile.

更新日期：2020-09-15

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南