Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 97, Issue -, Pages 19-31Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.04.043
Keywords
HSP70 inhibitors; Lapatinib-resistant breast cancer cell; Biological evaluation
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Funding
- National Natural Science Foundation of China [81473139]
- State Key Laboratory of Toxicology and Medical Countermeasures
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HSP70 is a potential target for tumour treatment. HSP70 plays significant roles in several biological processes, including the regulation of apoptosis. In this study, piperidine derivatives were designed as novel HSP70 inhibitors based on virtual fragment screening performed in Dock 4.0, Discovery Studio 2.5 and SYBYL 6.9. A total of 67 novel piperidine derivatives were synthesized. Cell viability assays were performed in 16 cancer cell lines. The emphasis was placed on lapatinib-resistant breast cancer cells (BT/LapR1.0, MDA-MB-361, SK/Lap(R)1.0, and MDA-MB-453). The compounds HSP70-36/37/40/43146 significantly inhibited the proliferation of human breast cancer cells. Compound HSP70-36 inhibited the growth of BT474 and BT/Lap(R)1.0 cells with IC50 values of 1.41 mu M and 1.47 mu M, respectively. The binding affinity of HSP70-36/HSP70 was evaluated by surface plasmon resonance and yielded K-d values of 2.46 mu M. The LD50 was 869.0 mgkg(-1). These data suggest that HSP70-36 may be a potential candidate compound for tumour treatment. (C) 2015 The Authors. Published by Elsevier Masson SAS.
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