El-Sayed Nahed Nasser Eid, Al-Otaibi Taghreed M, Barakat Assem, Almarhoon Zainab M, Hassan Mohd Zaheen, Al-Zaben Maha I, Krayem Najeh, Masand Vijay H, Ben Bacha Abir
Egyptian Drug Authority (EDA), 51 Wezaret El-Zeraa St., Giza 35521, Egypt.
Department of Chemistry, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Oct 1;16(10):1392. doi: 10.3390/ph16101392.
Oxidative stress, COX-2, LDHA and hyperglycemia are interlinked contributing pathways in the etiology, progression and metastasis of colon cancer. Additionally, dysregulated apoptosis in cells with genetic alternations leads to their progression in malignant transformation. Therefore, quinazolinones - and - were synthesized and evaluated as antioxidants, enzymes inhibitors and cytotoxic agents against LoVo and HCT-116 cells. Moreover, the most active cytotoxic derivatives were evaluated as apoptosis inducers. The results indicated that , and were efficiently scavenged DPPH radicals with lowered IC values (mM) ranging from 0.165 ± 0.0057 to 0.191 ± 0.0099, as compared to 0.245 ± 0.0257 by BHT. Derivatives , and were recognized as more potent dual inhibitors than quercetin against α-amylase and α-glucosidase, in addition to , , and - against α-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, and were identified as the most active derivatives. Molecular docking studies were used to elucidate the binding affinities and binding interactions between the inhibitors and their target proteins. Compounds and showed cytotoxic activities, with IC values (µM) of 294.32 ± 8.41 and 383.5 ± 8.99 (LoVo), as well as 298.05 ± 13.26 and 323.59 ± 3.00 (HCT-116). The cytotoxicity mechanism of and could be attributed to the modulation of apoptosis regulators (Bax and Bcl-2), the activation of intrinsic and extrinsic apoptosis pathways via the upregulation of initiator caspases-8 and -9 as well as executioner caspase-3, and the arrest of LoVo and HCT-116 cell cycles in the G2/M and G1 phases, respectively. Lastly, the physicochemical, medicinal chemistry and ADMET properties of all compounds were predicted.
氧化应激、COX-2、LDHA和高血糖是结肠癌病因、进展和转移过程中相互关联的促成途径。此外，基因改变的细胞中凋亡失调会导致其恶性转化进程。因此，合成了喹唑啉酮类化合物，并将其作为抗氧化剂、酶抑制剂和针对LoVo和HCT-116细胞的细胞毒剂进行评估。此外，对活性最高的细胞毒衍生物进行了凋亡诱导剂评估。结果表明，与BHT的0.245±0.0257相比，[具体化合物]能有效清除DPPH自由基，IC50值（mM）范围为0.165±0.0057至0.191±0.0099。除了[具体化合物]对α-淀粉酶有抑制作用外，[具体化合物]被认为是比槲皮素更有效的α-淀粉酶和α-葡萄糖苷酶双重抑制剂。尽管没有一种化合物对COX-2和LDHA的抑制效率高于参考抑制剂，但[具体化合物]被确定为活性最高的衍生物。分子对接研究用于阐明抑制剂与其靶蛋白之间的结合亲和力和结合相互作用。化合物[具体化合物]表现出细胞毒活性，LoVo细胞的IC50值（µM）为294.32±8.41和383.5±8.99，HCT-116细胞的IC50值为298.05±13.26和323.59±3.00。[具体化合物]的细胞毒性机制可能归因于凋亡调节因子（Bax和Bcl-2）的调节、通过上调起始半胱天冬酶-8和-9以及执行半胱天冬酶-3激活内源性和外源性凋亡途径，以及分别使LoVo和HCT-116细胞周期停滞在G2/M期和G1期。最后，预测了所有化合物的物理化学、药物化学和ADMET性质。
