Frontiers in Oncology (Aug 2022)

Design, synthesis, and anticancer activity of three novel palbociclib derivatives

  • Tian Li,
  • An-Di Zhou,
  • Li-Fei Bai,
  • Xiao-Yang Zhang,
  • Yu-Ting Zhou,
  • Hai-Li Yang,
  • Le-Tian Xu,
  • Xin-Qin Guo,
  • Xi-Yu Zhu,
  • Dong-Jin Wang,
  • Hong-Wei Gu,
  • Xiao-Ming Wang

DOI
https://doi.org/10.3389/fonc.2022.959322
Journal volume & issue
Vol. 12

Abstract

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Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

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