2. Academic Validation
  3. Structure-Activity Relationship Study of Rakicidins: Overcoming Chronic Myeloid Leukemia Resistance to Imatinib with 4-Methylester-Rakicidin A

Structure-Activity Relationship Study of Rakicidins: Overcoming Chronic Myeloid Leukemia Resistance to Imatinib with 4-Methylester-Rakicidin A

  • J Med Chem. 2016 Feb 11;59(3):1184-96. doi: 10.1021/acs.jmedchem.5b01841.
Feng Sang 1 2,  Yahui Ding 1,  Jinghan Wang 1,  Bingxia Sun 1,  Jianlei Sun 1,  Yan Geng 1 3,  Zhang Zhang 4,  Ke Ding 4,  Ling-Ling Wu 1 3,  Jian-Wei Liu 1,  Cuigai Bai 3,  Guang Yang 1,  Quan Zhang 1,  Lu-Yuan Li 1,  Yue Chen 1
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
  • 2 School of Life Sciences, Shandong University of Technology , Zibo 255049, People's Republic of China.
  • 3 High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
  • 4 State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science , 190 Kai Yuan Avenue, Guangzhou 510530, People's Republic of China.
PMID: 26814890 DOI: 10.1021/acs.jmedchem.5b01841
Abstract

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, 1a 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-Abl(T315I) 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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