设计并通过分子对接和生物学证据支持新型合成方法，获得萘醌-肼基三唑并噻二嗪类似物作为潜在的抑制拓扑异构酶-IIB 的抗癌药物。
Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB.
机构信息
Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt.
Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt; Biochemistry & Molecular Biology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
出版信息
Bioorg Chem. 2020 Mar;96:103641. doi: 10.1016/j.bioorg.2020.103641. Epub 2020 Jan 30.
A novel synthetic approach was developed for the synthesis of 3-hydrazinotriazolothiadiazines in just one step from Purpald and phenacyl bromides. They were then selectively tethered to naphthoquinone fragments through hydrazine moiety generating novel Naphthoquinone-hydrazinotriazolothiadiazine analogues. In vitro cytotoxicity for the synthesized chemical entities was validated against HepG2 and MCF-7 cell lines and recorded IC inhibitory profile range of 0.07-19.68 µM and 1.19-67.32 µM respectively. Among the synthesized series, compound 4c had maximal cytotoxicity against HepG2 and was therefore selected for further downstream biological investigations. Caspase 3 apoptotic marker was significantly upregulated in cells treated with compound 4c with induction of apoptosis at Pre-G1 phase and cell death at G2/M phase. Compounds 4a, 4c and 4d exhibited the most powerful inhibitory range (0.55-0.64 µM) against Topo IIB. Molecular docking study revealed potential interactions of those compounds within the ATP catalytic binding domain of Topo-IIB with high scores. In conclusion, the novel Naphthoquinone-hydrazinotriazolothiadiazine analogues could serve as promising anticancer agents through inhibition of Topoisomerase-IIB.
开发了一种新颖的合成方法，可从 Purpald 和苯甲酰溴一步合成 3-腙基三唑并噻二嗪。然后，它们通过腙部分选择性地连接到萘醌片段上，生成新型的萘醌-腙三唑并噻二嗪类似物。对合成的化学实体进行了体外细胞毒性验证，针对 HepG2 和 MCF-7 细胞系，并记录了 0.07-19.68 µM 和 1.19-67.32 µM 的 IC 抑制谱范围。在所合成的系列中，化合物 4c 对 HepG2 的细胞毒性最大，因此被选为进一步的下游生物学研究。用化合物 4c 处理的细胞中 caspase 3 凋亡标志物显著上调，并诱导细胞凋亡处于 Pre-G1 期和细胞死亡处于 G2/M 期。化合物 4a、4c 和 4d 对 Topo IIB 表现出最强的抑制范围（0.55-0.64 µM）。分子对接研究表明，这些化合物与 Topo-IIB 的 ATP 催化结合域具有潜在的相互作用，并具有较高的分数。总之，新型的萘醌-腙三唑并噻二嗪类似物可通过抑制拓扑异构酶 IIB 作为有前途的抗癌剂。
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