Design, synthesis, and bioevaluation of pyrazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potent anticancer activities

• DOI: 10.1016/j.ejmech.2020.112519
• Publication Date: 2020-06-27T23:19:30Z
• Authors: Gang Li; Yuxi Wang; Ling Li; Yichang Ren; Xin Deng; Jin Liu; Wei Wang; Meihua Luo; Shuwen Liu; Jianjun Chen
• Keywords: 0301 basic medicine; Binding Sites; Dose-Response Relationship, Drug; Molecular Structure; Swine; Antineoplastic Agents; Tubulin Modulators; Polymerization; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; Tubulin; Drug Design; Microsomes, Liver; Tumor Cells, Cultured; Animals; Humans; Pyrazoles; Drug Screening Assays, Antitumor; Colchicine; Cell Proliferation

A series of Pyrazolo[1,5-a]Pyrimidine analogs were designed and synthesized as novel tubulin inhibitors. Among them, compounds 1a and 1b showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 24.8 nM and 28 nM, respectively. We determined the crystal structures of 1a and 1b in complex with tubulin and confirmed their direct binding to the colchicine site. Compounds 1a and 1b also effectively inhibited tubulin polymerization in vitro, induced cell cycle arrest in G2/M phase, and inhibited cancer cell migration. In addition, compound 1b exhibited high metabolic stability in human liver microsomes. Finally, 1b was highly effective in suppressing tumor growth in a B16-F10 mouse melanoma model without apparent toxicity. In summary, these results suggest that 1b represents a promising tubulin inhibitor worthy of further investigation.