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Medicinal Chemistry Research

, Volume 27, Issue 5, pp 1355–1365 | Cite as

Synthesis, cytotoxic activity and binding model analysis of novel isoxazole-docetaxel analogues with C3′-N modification

  • Ming Chen
  • Jiyuan Liu
  • Zhen Tian
  • Xueying Liu
  • Shengyong Zhang
Original Research

Abstract

Structure–activity relationship (SAR) studies confirm that modifications at C-3′ position can lead to the development of highly potent novel taxoids. We designed and synthesized a series of novel isoxazole-docetaxel analogues A1A5 by introducing isoxazolyl groups to C3′-N position. All of the synthesized compounds exhibited similar to better cytotoxic activities than docetaxel against human cancer cell lines, Hela, A2780, A549, MCF-7, and SK-OV-3. These compounds also possessed higher inhibition than docetaxel against drug-resistant cancer cell lines, A2780-MDR and MCF-7-MDR. Binding model analysis of A1A5 molecule to microtubule (MT) showed that these compounds were anchored to the active site, explaining their inhibitory effects on MT in vitro. The calculated binding free energy values were in positive correlation with the IC50 values of A1A5 compounds against cancer cells. These results strongly support the statement that the introduction of isoxazolyl groups to C-3′ position indeed improves the cytotoxic activities of taxoids.

Keywords

Docetaxel Isoxazole Cytotoxic Inhibition Binding model analysis 

Notes

Acknowledgements

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (21172262), the Chinese National Science & Technology Major Project (grants 2010ZXJ0900X-007), the Foundation of the 309th hospital (2015MS-011), the National Natural Science Foundation of China (grant number 21503272) and the General Financial Grant from the China Postdoctoral Science Foundation (grant number 2015M572753).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2151_MOESM1_ESM.docx (4.1 mb)
Supplementary Information

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacyThe 309th hospital of PLABeijingChina
  2. 2.Department of Medicinal Chemistry, School of PharmacyFourth Military Medical UniversityXi’anChina
  3. 3.Key Laboratory of Plant Protection Resources & Pest Management of the Ministry of Education, College of Plant ProtectionNorthwest A&F UniversityYanglingChina

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