Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 16, Issue 17, Pages 3189-3202Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8ob00286j
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Funding
- National Natural Science Foundation of China [81673300]
- CAMS Initiative for Innovative Medicine [CAMS-I2M-2-004]
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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 mu M, PF50 > 10; 11, IC50 = 3.02 mu M, PF50 approximate to 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.
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