Synthesis and evaluation of biological and antitumor activities of 5,7-dimethyl- oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives as novel inhibitors of FGFR1

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 30; no. 6; pp. 961 - 966
• Main Authors: Ye, Faqing, Wang, Yuewu, Nian, Siyun, Wang, Yu, Chen, Di, Yu, Shufang, Wang, Sicen
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 02.11.2015
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer therapy; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; FGFR1; Humans; kinase inhibitor; Models, Molecular; Molecular Structure; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Structure-Activity Relationship; synthesis; synthesis; structure–activity relationship; kinase inhibitor; Cancer therapy; FGFR1
• ISSN: 1475-6366; 1475-6374
• DOI: 10.3109/14756366.2014.1002401

A series of 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives, N5a-5l, was designed, synthesized and evaluated for their FGFR1-inhibition ability as well as cytotoxicity against three cancer cell lines (H460, B16F10 and A549) in vitro. Several compounds displayed good-to-excellent potency against these cancer cell lines compared to SU5402. Structure-activity relationship analyses indicated that compounds with a rigid structure and more heteroatoms at the side chain of the parent ring were more effective than those without these substitutions. The compound N5g (37.4% FGFR1 inhibition at 1.0 μM) was identified to have the most potent antitumor activities, with IC 50 values of 5.472, 4.260 and 5.837 μM against H460, B16F10 and A549 cell lines, respectively. Together, our results suggest that 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives may serve as potential agents for the treatment of FGFR1-mediated cancers.