2201-24-3Relevant articles and documents
Novel 4,5-dihydrospiro[benzo[c]azepine-1,1′-cyclohexan]-3(2H)-one derivatives as PARP-1 inhibitors: Design, synthesis and biological evaluation
Li, Shuai,Li, Xin-yang,Zhang, Ting-jian,Zhu, Ju,Liu, Kai-li,Wang, De-pu,Meng, Fan-hao
, (2021/04/02)
To further explore the research of novel PARP-1 inhibitors, we designed and synthesized a series of novel amide PARP-1 inhibitors based on our previous research. Most compounds displayed certain antitumor activities against four tumor cell lines (A549, HepG2, HCT-116, and MCF-7). Specifically, the candidate compound R8e possessed strong anti-proliferative potency toward A549 cells with the IC50 value of 2.01 μM. Compound R8e had low toxicity to lung cancer cell line. And the in vitro enzyme inhibitory activity of compound R8e was better than rucaparib. Molecular docking studies provided a rational binding model of compound R8e in complex with rucaparib. The following cell cycle and apoptosis assays revealed that compound R8e could arrest cell cycle in the S phase and induce cell apoptosis. Western blot analysis further showed that compound R8e could effectively inhibit the PAR's biosynthesis and was more effective than rucaparib. Overall, based on the biological activity evaluation, compound R8e could be a potential lead compound for further developing novel amide PARP-1 inhibitors.
Design, synthesis and biological evaluation of homoerythrina alkaloid derivatives bearing a triazole moiety as PARP-1 inhibitors and as potential antitumor drugs
Li, Shuai,Li, Xin-yang,Zhang, Ting-jian,Kamara, Mohamed Olounfeh,Liang, Jing-wei,Zhu, Ju,Meng, Fan-hao
, (2019/11/11)
A series of homoerythrina alkaloid derivatives containing a 1,2,3-triazole moiety as PARP-1 inhibitors were designed and synthesized. And their anti-proliferative activity was further evaluated. Compound 10n had excellent activity to inhibit proliferation of A549 cells (IC50 = 1.89 μM), which was higher than harringtonine (IC50 = 10.55 μM), pemetrexed (IC50 = 3.39 μM), and rucaparib (IC50 = 4.91 μM). Furthermore, the selectivity index of compound 10n was higher than rucaparib and pemetrexed for lung cancer cells. Flow cytometry analysis showed that compound 10n significantly arrested the cell cycle in the S phase, then induced apoptosis of A549 cells (apoptosis rate is 46%), which effectively inhibited cell proliferation. Simultaneously, western blot analysis revealed that compound 10n could prevent the biosynthesis of PAR. Further analysis results revealed that compound 10n could inhibit the expression of cyclin A, down-regulate the expression of bcl-2/bax, activate caspase-3, and ultimately induce apoptosis of A549 cells. All the results indicated that compound 10n had potential research value as a novel PARP-1 inhibitor in antitumor, and it provided a new reference for further development of PARP-1 inhibitors.
1-azaspiro[5.5]undecyl-3-one and 1-azaspiro[5.5]undecyl-3-alcohol compounds
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, (2020/05/30)
The invention belongs to the technical field of medicines, and particularly relates to 1-azaspiro[5.5]undecyl-3-one and 1-azaspiro[5.5]undecyl-3-alcohol compounds and a preparation method and application thereof. The general formulas of the 1-azaspiro[5.5]undecyl-3-one compound and the 1-azaspiro[5.5]undecyl-3-alcohol compounds are shown in a formula I and a formula II in the specification. A six-membered spiro structure is synthesized for the first time, a brand-new compound with a better anti-tumor effect is obtained, and pharmacological research shows that the compound has certain inhibitory activity on human colon cancer HCT-116 cells. The preparation method of the 1-azaspiro[5.5]undecyl-3-one compound and the 1-azaspiro[5.5]undecyl-3-alcohol compound is simple and feasible, the yieldis relatively good, and the method is suitable for industrial production.
