期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 3, 页码 1184-1196出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01841
关键词
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资金
- National Natural Science Foundation of China (NSFC) [21372129, 8157328, 81370086, 81573308]
- Program for New Century Excellent Talents in University
- Hundred Young Academic Leaders Program of Nankai University
- General Financial Grant from the China Postdoctoral Science Foundation [2015M571261]
Natural product rakicidin A induces cell death in TKI-resistant chronic myelogenous leukemia (CML) cells. Therefore, 14 rakicidin A analogues were synthesized via a highly efficient combinatorial strategy and were evaluated against CML cell lines. The conjugated diene moiety was found to be crucial for the anti-CML activity of rakicidin A, and the changes in the configuration(s) at C-2, C-3, C-14, C-15, and C-16 resulted in lower levels of anti-CML activity. The most promising compound was 4-methylester rakicidin A (1a). Compared with rakicidin A, la exhibited 2.8-fold greater potency against the imatinib-resistant cell line K562/G(+) and approximately 100-fold enhanced potency compared with that of imatinib. Furthermore, compound 1a demonstrated a significantly lower resistance index against Ba/F3 cells expressing BCR-ABLT(315I) than bosutinib, dasatinib, nilotinib, and ponatinib, while 1a exhibited less effect on normal hematopoietic cells. Preliminary results indicated that 1a down-regulated caspase-3 and PARP, which contributes to its K562 cell inhibitory activity.
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