Exploring the Structure–Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug-Resistant Cancer Cells

Multidrug resistance (MDR) is one
major barrier in cancer management,
which urges for new drugs to help treat MDR malignancies and elucidate
MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate
increased antiproliferative activity toward MDR acute-myeloid-leukemia
(AML) cells. The structure–activity relationship (SAR) of the
antiproliferative potency has been partly characterized, whereas the
structural determinants contributing to selectivity have not been
investigated. In this study, three series of CXL compounds were synthesized
and evaluated in HL60 and HL60/MX2 leukemia cells. The results not
only confirmed previous SAR studies but also, for the first time,
provided structural insights into the selectivity for MDR HL60/MX2
cells. Using the lead compounds as probes, we demonstrated that their
modulation of intracellular-calcium homeostasis results in their antiproliferative
potency and selectivity. Three candidates also demonstrate excellent
in vitro safety profiles between cancer cells and normal cells, which
will be evaluated in vivo in future studies.