C6取代苯并[4,5]咪唑并[1,2-a]喹喔啉衍生物的简便合成及其抗癌评价,Archiv der Pharmazie

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C6取代苯并[4,5]咪唑并[1,2-a]喹喔啉衍生物的简便合成及其抗癌评价
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2021-03-22 , DOI: 10.1002/ardp.202000393
Rahul Singh ₁ , Ravinder Kumar ₁ , Mallesh Pandrala ₂ , Parleen Kaur ₁ , Saloni Gupta ₃ , Dhanir Tailor ₂ , Sanjay V Malhotra ₂ , Deepak B Salunke _{1,

4}

Affiliation

癌症仍然是世界范围内的主要死亡原因，导致人们不断努力发现和开发高效的抗癌药物。杂环化合物库的高通量筛选是一种很有前途的方法，它提供了几种具有新作用机制的新先导分子。基于咪唑喹喔啉的抗癌潜力以及结构相似的咪唑喹啉衍生支架，我们制备了一组 C6 取代的苯并咪唑 [1,2- a] 喹喔啉衍生物通过两种新的合成路线，使用市售的起始材料，具有良好到极好的产率，并评估了它们对 NCI-60 癌细胞系的抗癌活性。NCI-60 细胞系面板中合成化合物的单剂量 (10 µM) 抗癌筛选显示，取代基在活性中具有重要作用。特别是，吲哚 ( 7f )、咪唑 ( 7g ) 和苯并咪唑 ( 7h ) 衍生物对三阴性乳腺癌细胞系 MDA-MB-468 显示出显着的活性。先导化合物也表现出显着的 IC ₅₀对另一种乳腺癌细胞系 MCF-7 的值。此外，观察到这些化合物对正常细胞系无毒：HEK293（人胚胎肾细胞系）和 MCF12A（非致瘤性人乳腺上皮细胞系）。对健康细胞的 IC ₅₀值至少高出 5 到 11 倍，提供了一类新的杂环化合物，可以进一步开发为有前途的癌症治疗方法。

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Facile synthesis of C6-substituted benz[4,5]imidazo[1,2-a]quinoxaline derivatives and their anticancer evaluation

Cancer remains a leading cause of death worldwide, resulting in continuous efforts to discover and develop highly efficacious anticancer drugs. High-throughput screening of heterocyclic compound libraries is one of the promising approaches that provided several new lead molecules with a novel mechanism of action. On the basis of the promising anticancer potential of imidazoquinoxaline as well as the structurally similar imidazoquinoline-derived scaffold, we prepared a set of C6-substituted benzimidazo[1,2-a]quinoxaline derivatives via two novel synthetic routes using commercially available starting materials, with good to excellent yields and evaluated their anticancer activity against the NCI-60 cancer cell lines. The one-dose (10 µM) anticancer screening of the synthesized compounds in the NCI-60 cell line panel revealed that the substituents have a significant role in the activity. In particular, the indole (7f), imidazole (7g), and benzimidazole (7h) derivatives showed significant activity against the triple-negative breast cancer cell line, MDA-MB-468. The lead compounds also exhibited notable IC₅₀ values against another breast cancer cell line, MCF-7. Furthermore, it was observed that these compounds were relatively nontoxic to normal cell lines: HEK293 (human embryonic kidney cell line) and MCF12A (nontumorigenic human breast epithelial cell line). The IC₅₀ values against healthy cells were at least 5- to 11-fold higher, offering a new class of heterocycles that can be further developed as promising therapeutics for cancer treatment.

更新日期：2021-03-22

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