Abstract：
The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric properties similar to trans-cinnamaldehyde (styrylaldehyde), a safe natural compound that exhibited interesting activities against various cancers. We synthesized a series of compounds that differ structurally in having different alkyl, aryl and heterocyclic substituents at the N3 position of the 2-styryl-4-imidaolone pharmacophore. The compounds were assayed for their cytotoxicity against both cancer and normal cell lines. In addition, their cellular mechanism of action as reactive oxygen species (ROS) inducers were investigated. Many of the synthesized compounds showed higher activities on colon, breast and hepatic cancer cell lines than the parent trans-cinnamaldehyde. Compounds 3a and 3e showed selective antiproliferative activity against cancer cell lines at low micromolar to sub-micromolar IC50 value. Compounds were extremely less toxic on normal cell lines baby hamster kidney fibroblasts (BHK) and human lung tissue fibroblast (WI-38). Similar to trans-cinnamaldehyde, the colon cancer cell cycle analysis indicated cell cycle changes consistent with increased oxidative stress leading to apoptosis. Compound 3e caused elevation of all cell oxidative indicators of ROS such as a decrease in reduced glutathione, increased malondialdehyde and suppression of catalase and superoxide dismutase activities. Dihydroethidium staining, nuclear fragmentation and increased caspase-3 further confirmed extensive apoptotic induction due to ROS accumulation upon treatment of human colon adenocarcinoma (HCT116) cells with compounds 3a and 3e. Changes in human breast adenocarcinoma (MCF7) cells were less revealing for ROS induction and increased oxidative stress.
CONCLUSIONS: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.
CONCLUSIONS: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.
摘要：
2-苯乙烯基-3,5-二氢-4H-咪唑-4-酮可能被认为是具有类似于反式肉桂醛（苯乙烯醛）的等排性质的系统，一种安全的天然化合物，对各种癌症表现出有趣的活性。我们合成了一系列结构不同的化合物，它们具有不同的烷基，在2-苯乙烯基-4-咪唑酮药效团的N3位的芳基和杂环取代基。测定化合物对癌症和正常细胞系的细胞毒性。此外,研究了它们作为活性氧（ROS）诱导剂的细胞作用机制。许多合成的化合物对结肠显示出更高的活性，乳腺癌和肝癌细胞系比亲本反式肉桂醛。化合物3a和3e在低的微摩尔至亚微摩尔IC50值下显示出针对癌细胞系的选择性抗增殖活性。化合物对正常细胞系幼仓鼠肾成纤维细胞(BHK)和人肺组织成纤维细胞(WI-38)的毒性极低。类似于反式肉桂醛，结肠癌细胞周期分析表明细胞周期变化与氧化应激增加导致细胞凋亡一致.化合物3e引起ROS的所有细胞氧化指标的升高，例如还原型谷胱甘肽的减少，增加丙二醛和抑制过氧化氢酶和超氧化物歧化酶活性。二氢乙锭染色,在用化合物3a和3e处理人结肠腺癌(HCT116)细胞时,由于ROS积累,核片段化和增加的半胱天冬酶-3进一步证实了广泛的凋亡诱导。人乳腺癌（MCF7）细胞的变化很少显示ROS诱导和氧化应激增加。
结论:这些化合物代表了将天然化合物有效地重新骨架成高效药物样类似物的实例。
结论:这些化合物代表了将天然化合物有效地重新骨架成高效药物样类似物的实例。
