Jump to main content
Jump to site search

Issue 17, 2018
Previous Article Next Article

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

Author affiliations

Abstract

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.

Graphical abstract: Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity

Back to tab navigation

Supplementary files

Publication details

The article was received on 03 Feb 2018, accepted on 05 Apr 2018 and first published on 06 Apr 2018


Article type: Paper
DOI: 10.1039/C8OB00286J
Citation: Org. Biomol. Chem., 2018,16, 3189-3202
  •   Request permissions

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

    J. Zhou, M. Ji, H. Yao, R. Cao, H. Zhao, X. Wang, X. Chen and B. Xu, Org. Biomol. Chem., 2018, 16, 3189
    DOI: 10.1039/C8OB00286J

Search articles by author

Spotlight

Advertisements