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

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• 作者：Feng Sang ; Yahui Ding ; Jinghan Wang ; Bingxia Sun ; Jianlei Sun ; Yan Geng ; Zhang Zhang ; Ke Ding ; Ling-Ling Wu ; Jian-Wei Liu ; Cuigai Bai ; Guang Yang ; Quan Zhang ; Lu-Yuan Li ; Yue Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1184-1196
• 全文大小：576K
• ISSN：1520-4804

文摘

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.