Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives

• Published in: European journal of medicinal chemistry 2018-01, Vol.143, p.1396-1405
• Main Authors: Li, Zhong-Hua, Zhao, Tao-Qian, Liu, Xue-Qi, Zhao, Bing, Wang, Chao, Geng, Peng-Fei, Cao, Ya-Quan, Fu, Dong-Jun, Jiang, Li-Ping, Yu, Bin, Liu, Hong-Min
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis; Apoptosis - drug effects; Cell cycle arrest; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Drug Design; Drug Screening Assays, Antitumor; Humans; Pteridin-7(8H)-one; Pteridines - chemical synthesis; Pteridines - chemistry; Pteridines - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.10.037

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8H)-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC50 values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established. Pteridin-7(8H)-ones were synthesized and evaluated for their antiproliferative activity. Compound 12 displayed acceptable growth inhibition, induced apoptosis of MKN-45 cells. Besides, a novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold was first prepared. [Display omitted] •The pteridin-7(8H)-one derivatives showed potent inhibition against the cancer cells.•Compound 12 exerted the most potent and broad-spectrum antiproliferative activity.•Compound 12 induced the apoptosis and G2/M arrest of MKN-45 cells.•A novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold was constructed.