University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia 11566, Cairo, Egypt.
Hormonal Evaluation Department, National Organization for Drug Control & Research (NODCAR), Cairo, Egypt.
Anticancer Agents Med Chem. 2019;19(5):620-626. doi: 10.2174/1871520619666190225122338.
In a continuous combat against cancer, which is one of the leading causes of mortality now, chalcone and Schiff bases moieties have been incorporated and their antiproliferative activities and associated mechanisms against liver (HepG2) and breast (MCF-7) cell lines in addition to normal fibroblasts (WI-38) have been examined.
Derivatives 4 and 5 of Schiff bases only and chalcone derivatives of Schiff bases 1 and 2 were devoid of any antiproliferative activity. All three compounds (3, 6, and 7) with significant antiproliferative activity were selective and caused no growth inhibition in normal fibroblasts. Derivative 3 was a chalcone only with IC50 of ~20 µM and has a very interesting signature where it enhanced apoptosis in HepG2 by stimulating the expression of downstream execution caspase 3 without affecting neither p53 nor initiator caspase 9. In spite of the structural similarity between compounds 6 and 7, compound 6 discerned itself with a unique IC50 of ~ 10 µM.
The antiproliferative activity of derivative 6 could be attributed to its unique capability of formation of free radicals such as phenoxide radicals which arrested the cell cycle through enhancing the expression of p53 and induced apoptosis by induction of both caspases 9 and 3. It was the only investigated derivative that inhibited the tyrosine kinase activity by 89%.
The antiproliferative activity of the compounds under investigation considerably depended on the nature of the substituent at position 4 in phenyl rings of both chalcone and Schiff base fragments. Derivative 6 with electron withdrawing chlorine substitution on the phenyl ring of Schiff base fragment and an electron donating methoxy group on the phenyl ring of chalcone fragment was the most active member.
在与癌症的持续斗争中，癌症是目前主要的死亡原因之一，人们将查尔酮和席夫碱部分结合起来，研究它们对肝癌（HepG2）和乳腺癌（MCF-7）细胞系以及正常成纤维细胞（WI-38）的增殖活性和相关机制。
只有席夫碱衍生物 4 和 5 以及查尔酮衍生物 1 和 2 没有任何增殖活性。所有三种具有显著增殖活性的化合物（3、6 和 7）都是选择性的，不会导致正常成纤维细胞生长抑制。衍生物 3 是一种只有查尔酮的化合物，IC50 约为 20µM，具有非常有趣的特征，它通过刺激下游执行 caspase 3 的表达来增强 HepG2 细胞的凋亡，而不影响 p53 或起始 caspase 9。尽管化合物 6 和 7 之间存在结构相似性，但化合物 6 以独特的 IC50（约 10µM）脱颖而出。
衍生物 6 的增殖活性可以归因于其形成自由基（如酚氧自由基）的独特能力，这些自由基通过增强 p53 的表达和诱导 caspase 9 和 3 的诱导来阻止细胞周期并诱导细胞凋亡。它是唯一一种被研究的衍生物，能够抑制 89%的酪氨酸激酶活性。
研究化合物的增殖活性在很大程度上取决于查尔酮和席夫碱片段苯环上 4 位取代基的性质。具有席夫碱片段上吸电子氯取代基和查尔酮片段上供电子甲氧基取代基的衍生物 6 是最活跃的成员。
