Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity†,Organic & Biomolecular Chemistry

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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10和11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，IC₅₀ = 3.02μM，PF₅₀ ≈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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