Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents.
Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents.
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作为抗癌剂的新型芘基衍生物的设计、合成和生物学评价。
DOI：
10.1016/j.ejmech.2014.09.072
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发表时间：
2015
影响因子：
6.7
通讯作者：
Banik,BimalK
中科院分区：
文献类型：
--
作者：
Bandyopadhyay,Debasish;Sanchez,JorgeL;Guerrero,AdrianM;Chang,Fang-Mei;Granados,JoseC;Short,JohnD;Banik,BimalK
多环芳烃广泛存在于自然界中，毒性范围从无毒到剧毒。采用四步策略合成了一系列芘衍生物，其中芘核通过碳连接体与碱性杂环部分相连。并对其理化性质和可药用性进行了虚拟筛选。化合物（1-8）的细胞毒性已经在体外针对一小组人癌细胞系进行了评价，所述人癌细胞系包括两种肝癌（HepG 2和Hepa 1-6）、两种结肠癌（HT-29和Caco-2）以及宫颈癌（HeLa）和乳腺癌（MCF-7）细胞系各一种。IC 50数据表明化合物6和8是本发明芘基衍生物组中最有效的细胞毒性剂，表明具有4-碳连接体比5-碳连接体更有效，并且连接体中酰胺羰基的存在严重降低了化合物的功效。与正常肝细胞相比，化合物在较低剂量（<5 μM）下显示出对癌细胞的选择性。作用机制支持细胞通过凋亡以半胱天冬酶非依赖性方式死亡，而不裂解聚（ADP-核糖）聚合酶（PARP），即使化合物引起质膜形态学变化。这些化合物，无论是高细胞毒性还是轻度细胞毒性，都定位于细胞膜。在侧链中具有哌啶环（6）或N-甲基哌嗪（8）的化合物均能够规避过表达P-糖蛋白的SKOV 3-MDR 1-M6/6卵巢癌细胞的耐药性。定性构效关系也进行了研究。
Polycyclic aromatic hydrocarbons are widespread in nature with a toxicity range from non-toxic to extremely toxic. A series of pyrenyl derivatives has been synthesized following a four-step strategy where the pyrene nucleus is attached with a basic heterocyclic moiety through a carbon linker. Virtual screening of the physicochemical properties and druggability has been carried out. The cytotoxicity of the compounds (1–8) have been evaluatedin vitroagainst a small panel of human cancer cell lines which includes two liver cancer (HepG2 and Hepa 1–6), two colon cancer (HT-29 and Caco-2) and one each for cervical (HeLa) and breast (MCF-7) cancer cell lines. The IC50data indicate that compound6and8are the most effective cytotoxic agents in the present set of pyrenyl derivatives, suggesting that having a 4-carbon linker is more effective than a 5-carbon linker and the presence of amide carbonyl groups in the linker severely reduces the efficacy of the compound. The compounds showed selectivity toward cancer cells at lower doses (<5 μM) when compared with the normal hepatocytes. The mechanism of action supports the cell death through apoptosis in a caspase-independent manner without cleavage of poly (ADP-ribose) polymerase (PARP), even though the compounds cause plasma membrane morphological changes. The compounds, whether highly cytotoxic or mildly cytotoxic, localize to the membrane of cells. The compounds with either a piperidine ring (6) or anN-methyl piperazine (8) in the side chain were both capable of circumventing the drug resistance in SKOV3-MDR1-M6/6 ovarian cancer cells overexpressing P-glycoprotein. Qualitative structure-activity relationship has also been studied.