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

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-ABLT315I 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.