Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity
Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity
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DOI：
10.1016/j.ejmech.2021.113609
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发表时间：
2021-06-11
影响因子：
6.7
通讯作者：
Arafa，Reem K.
中科院分区：
文献类型：
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作者：
ElZahabi，Heba S. A.;Nafie，Mohamed S.;Arafa，Reem K.
本工作设计并合成了一系列新的喹唑啉-4-酮类化合物，基于喹唑啉类小分子作为抗癌药物的有效性。合成的化合物对MCF-7的抑制作用强于A-549，其IC50为低至亚微摩尔。药物17的IC50与阳性对照阿霉素相当(IC50=0.06μM)，优于5-氟尿嘧啶(IC50=2.13μM)。化合物17进一步对MDA-MB-231和MCF-10A进行了测试，发现化合物17对MCF-7的细胞毒性是后者的2倍。17诱导MCF-7细胞发生明显的凋亡活性，增加了细胞的凋亡性，同时诱导细胞周期停滞于前G1期和G1期。类似地，17能够诱导MD-MB-231处理的细胞凋亡，并与细胞周期的中断有关，导致细胞停滞于前G1期和S期。对MCF-7细胞基因表达的研究表明，促凋亡基因P53、PUMA、Bax、caspase3、8和9的表达增加，而抗凋亡基因bcl2的表达降低。此外，17减少了自噬，让位于细胞凋亡，从而诱导癌细胞死亡。后一种观察结果与EGFR及其下游效应因子PI3K、AKT和mTOR下调有关。作为其生物分子靶点，17也抑制了与厄洛替尼类似的EGFR(IC_(50)分别为0.072和0.087μM)。此外，在乳腺癌小鼠模型的活体测试中，确认了17的抗肿瘤效果。最后，17与EGFR-ATP结合位点的对接证明了其与类似于厄洛替尼的EGFR结合的能力。
This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC50s. Compound17exhibited the best IC50being equipotent with the positive control doxorubicin (IC50 =0.06 μM) and better than 5-fluorouracil (IC50 =2.13 μM). Compound17was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by17on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly,17was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also,17reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target,17also inhibited EGFR similar to erlotinib (IC50= 0.072 and 0.087 μM, respectively). Additionally,in vivotesting in a mouse model of breast cancer affirmed the anti-tumor efficacy of17. Finally, docking of17against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib.