A series of novel
N
-alkyl-
N
-hydroxyl carboximates derived from
β
-elemene were fortuitously discovered. Most of them showed more potent anti-proliferative activities than their lead compound
β
-elemene (
1
). Notably, compound
11i
exhibited significant inhibitory effects on the proliferation of three lung cell lines (H1975, A549 and H460) and several other tumour cell lines (H1299, U87MG, MV4-11, and SU-DHL-2). Preliminary mechanistic studies revealed that compound
11i
could significantly induce cell apoptosis. Further
in vivo
study in the H460 xenograft mouse model validated the anti-tumour activities of
11i
with a greater tumour growth inhibition (TGI, 68.3%) than
β
-elemene and SAHA (50.1% and 55.9% respectively) at 60 mg/kg ip dosing, without obvious body weight loss and toxicity. Thus, such
N
-alkyl-
N
-hydroxyl carboximate class of compounds exemplified as
11i
demonstrated potent anticancer activities both
in vitro
and
in vivo
, and should warrant further investigation for potential anticancer therapy.
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3‐d]pyrimidine and pyrrolo[2,3‐b]pyridine scaffolds. Compound B3 {(E)‐3‐(4‐(((1‐(7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl)piperidin‐4‐yl)amino)methyl)phenyl)‐N‐hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 μM, against MV‐4‐11, K562, and WSU‐DLCL‐2 cells, respectively) with two‐ to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU‐DLCL‐2 cells revealed that B3 exhibits anticancer effects through the induction of G0/G1‐phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.
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