新型抗肿瘤双 1,4-二氢吡啶衍生物的分子研究及其对正常黑素细胞的有限副作用。
Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes.
机构信息
Chemistry Department (biochemistry branch), Faculty of Science, Cairo University, Giza, Egypt.
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt.
出版信息
Anticancer Agents Med Chem. 2018;18(15):2156-2168. doi: 10.2174/1871520618666181019095007.
BACKGROUND
Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila.
OBJECTIVE
The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer.
METHOD
An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated.
RESULTS
All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity.
CONCLUSION
we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.
背景
癌症是一种复杂的遗传疾病，其特征是细胞生长异常、侵袭和扩散到身体的其他部位。有几个因素会导致癌症，因为它们会导致 DNA 损伤和修复功能受损。使用化疗药物治疗癌症会产生毒副作用，因为它们对癌细胞缺乏特异性，也会影响正常细胞。此外，癌细胞可以抵抗化疗药物，使其无效。出于这些原因，人们非常关注开发副作用有限的新药，以减少癌症对化疗药物的耐药性。最近，一些 1,4-二氢吡啶衍生物被报道为多药耐药（MDR）调节剂，可抑制负责药物无法进入癌细胞的 p-糖蛋白。此外，当在果蝇身上研究时，1,4-DHPs 具有通过调节 DNA 修复来对抗化学物质的致突变作用。
目的
本研究的目的是合成含有酯基和醚键的双 1,4-DHPs，并评估新化合物的抗癌活性，以达到协同作用。为了了解该化合物对肺癌的作用机制，我们使用了不同的遗传工具。
方法
采用一锅法高效合成了 3-氨基巴豆腈和双（醛）的双 1,4-DHPs。评估了对人细胞系 MCF7 和 A549 细胞系的细胞毒性作用。
结果
所有化合物对肺癌细胞系（A549）的细胞毒性均优于乳腺癌细胞系。对于肺癌细胞系（A549），化合物 10 是最活跃的化合物，另外三个化合物 7、8 和 9 的 IC 值相当。对于乳腺癌细胞系（MCF7），最活跃的化合物是 7，而 8 记录的活性最低。
结论
我们开发了一种高效合成新型双 1,4-二氢吡啶衍生物的方法，其中包含酯或醚键。所有化合物对 A549 的细胞毒性均优于 MCF7，因此选择肺癌细胞系进行分子研究。结果表明，所有化合物（7、8、9 和 10）均使细胞周期停滞在 G1 期。CDK2 的分子对接研究证实了细胞周期测定的结果，表明化合物与酶的活性位点具有良好的结合能，表明对酶的抑制作用。
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