2. Academic Validation
  3. Design, synthesis and biological evaluation of dual Topo II/HDAC inhibitors bearing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs

Design, synthesis and biological evaluation of dual Topo II/HDAC inhibitors bearing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs

  • Eur J Med Chem. 2023 Apr 5;252:115303. doi: 10.1016/j.ejmech.2023.115303.
Mengmiao Zhao 1,  Kan Yang 1,  Xinyue Zhu 1,  Tian Gao 1,  Wei Yu 1,  Han Liu 1,  Zhihao You 1,  Zhenming Liu 2,  Xiaoqiang Qiao 3,  Yali Song 4
Affiliations

Affiliations

  • 1 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 3 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
  • 4 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
PMID: 36996717 DOI: 10.1016/j.ejmech.2023.115303
Abstract

Both Topoisomerase II (Topo II) and histone deacetylase (HDAC) are important therapeutic targets for Cancer. In this study, two series of novel compounds containing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs were designed and synthesized as dual Topo II/HDAC inhibitors. MTT assay indicated that all the compounds displayed potential antiproliferative activity against three Cancer cell lines (MGC-803, MCF-7 and U937) and low cytotoxicity on normal cell line (3T3). In the Enzyme activity inhibition experiments, compounds 7d and 8d exhibited excellent dual inhibitory activities against Topo II and HDAC. Cleavage reaction assay showed that 7d was a Topo II poison, which was consistent with the docking results. Further experimental results revealed that compounds 7d and 8d could promote Apoptosis and significantly inhibit the migration in MCF-7 cells. Molecular docking showed that compounds 7d and 8d bind Topo II and HDAC at the active sites. Molecular dynamics simulation showed that 7d can stably bind to Topo II and HDAC.

Keywords

Anticancer activity; Dual-target inhibitor; Histone deacetylase; Topoisomerase II.

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