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Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity†
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2018-04-06 00:00:00 , DOI: 10.1039/c8ob00286j
Jie Zhou 1, 2, 3, 4, 5 , Ming Ji 2, 3, 4, 5, 6 , Haiping Yao 1, 2, 3, 4, 5 , Ran Cao 1, 2, 3, 4, 5 , Hailong Zhao 1, 2, 3, 4, 5 , Xiaoyu Wang 1, 2, 3, 4, 5 , Xiaoguang Chen 2, 3, 4, 5, 6 , Bailing Xu 1, 2, 3, 4, 5
Affiliation  

Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure–activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10−9 M level and against PARP-2 at the 10−8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3.12 μM, PF50 > 10; 11, IC50 = 3.02 μM, PF50 ≈ 10). In vivo tumor growth inhibition was investigated using compound 11 in combination with TMZ, and it was demonstrated that compound 11 could strongly potentiate the cytotoxicity of TMZ in a MX-1 xenograft tumor model. The co-crystal structure of compound 11 complexed with PARP-1 was achieved and demonstrated a unique binding mode.

中文翻译:

喹唑啉-2,4(1 H,3 H)-二酮衍生物作为新型PARP-1 / 2抑制剂的发现:设计,合成及其抗肿瘤活性

设计并合成了带有3-氨基吡咯烷部分的新型喹唑啉-2,4(1 H,3 H)-二酮衍生物,并将其作为PARP-1 / 2抑制剂合成。检查了结构与活性之间的关系,发现许多有效的PARP-1 / 2抑制剂对PARP-1的选择性比PARP-2中等。这些化合物在10 -9 M水平下具有针对PARP-1的IC 50值,在10 -8 M水平下具有针对PARP-2的IC 50值。在所有合成的化合物中,化合物1011在MX-1细胞中均具有较强的细胞毒性,可单独使用或与替莫唑胺(TMZ)结合使用(10,IC 50 <3.12μM,PF50 > 10; 11,IC 50 = 3.02μM,PF 50 ≈10)。使用化合物11与TMZ联合研究了体内肿瘤生长抑制作用,并证明了化合物11可以在MX-1异种移植肿瘤模型中强烈增强TMZ的细胞毒性。获得了与PARP-1络合的化合物11的共晶体结构,并证明了其独特的结合模式。
更新日期:2018-04-06
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