一锅法合成螺（吲哚啉-3,4'-吡唑并[3,4-b]吡啶）-5'-碳腈作为 p53-MDM2 相互作用抑制剂。
One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
出版信息
Future Med Chem. 2018 Dec;10(24):2771-2789. doi: 10.4155/fmc-2018-0288. Epub 2018 Dec 10.
AIM
Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives.
MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies.
RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.
目的
抑制 P53-mdm2 相互作用将导致癌细胞凋亡。这一策略是通过报道的螺环-氧吲哚衍生物实现的。
材料与方法
合成了螺（吲哚啉-3,4'-吡唑并[3,4-b]吡啶）-5'-腈衍生物（4a-i 和 9a，b），并对其体外抗癌活性进行了筛选。对最活跃的化合物进行了 P53-MDM2 抑制活性、凋亡和分子对接研究。
结果与讨论
化合物 4d 表现出强大而广谱的增殖抑制活性，全谱 GI（MG-MID）值为 3.97 μM。化合物 4d 和 4i 分别以 IC = 52.1 和 95.2 nM 的抑制 p53-MDM2 蛋白-蛋白相互作用。化合物 4d 在分子水平上抑制 MCF-7 中野生型 p53 的表达，优于 MDA-MB231 中突变型 p53 的表达。分子对接研究说明了靶螺环-氧吲哚与 MDM2 上 p53 结合位点的可能相互作用。
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