title: Novel pyrazolo[3,4-d]pyrimidine derivatives as potential antitumor agents: exploratory synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.
abstract: In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC₅₀ for A549 cells was 2.24 µM, compared with an IC₅₀ of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: He
authors.forename: Jin-Ni
authors.initials: JN
authors.lastname: Zhao
authors.forename: Ruo
authors.initials: R
authors.lastname: Jia
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines