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Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-04-26 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01563
Erica Salvati 1 , Lorenzo Botta 2 , Jussara Amato 2 , Francesco Saverio Di Leva 2 , Pasquale Zizza 1 , Antimo Gioiello 3 , Bruno Pagano 2 , Grazia Graziani 4 , Madalena Tarsounas 5 , Antonio Randazzo 2 , Ettore Novellino 2 , Annamaria Biroccio 1 , Sandro Cosconati 6
Affiliation  

G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.

中文翻译:

双重G-四链体稳定剂和聚(ADP-核糖)聚合酶(PARPs)抑制剂的领先发现:抗癌治疗的新途径

G-四链体稳定剂是抗癌化疗的既定机会。为了规避G4配体的抗增殖作用,癌细胞在端粒募集PARP酶。在本文中,从我们小组先前发现的有效G4配体和同类PARP抑制剂的结构相似性出发,合成了一个衍生物库以发现第一个双重G4 / PARP配体。我们证明适当装饰的thieno [3,2 - c ] quinolin-4(5 H)-一个稳定体外和在细胞中的G4折叠,诱导定位于端粒的DNA损伤反应,抑制细胞中的PARylation,并具有在BRCA2缺陷型肿瘤细胞中具有抗增殖作用。
更新日期:2017-05-02
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