Abstract
A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.
Highlights
From ancient times, various natural products have been used as traditional medicines and are rich sources of bioactive compounds[1,2]
Chromones (4H-chomen-4-one, 4H-1-benzopyran-4-one) are widely distributed oxygen-containing natural heterocyclic compounds from the plants of Polygonaceae, Umbelliferae, Sterculiaceae, Rhamnaceae, Liliaceae, Asteraceae etc., with a benzoylated c-pyrone ring which is a part of the structure of flavonoid skeletons[3,4,5]
The cells were placed in six-well plates and incubated at 37 C for 24 h, after which K562 cells were treated with different concentrations (0, 0.8, 1.6, 3.2 mM) of 15a for 24 h, washed with PBS, centrifuged, and collected. 500 mL of binding buffer suspension cells, 5 mL of Annexin V-FITC, and 5 mL of propidium iodide (PI) were mixed incubated at room temperature, protected from light, and reacted for 5–15 min, Scheme 1
Summary
Various natural products have been used as traditional medicines and are rich sources of bioactive compounds[1,2]. Chromones (4H-chomen-4-one, 4H-1-benzopyran-4-one) are widely distributed oxygen-containing natural heterocyclic compounds from the plants of Polygonaceae, Umbelliferae, Sterculiaceae, Rhamnaceae, Liliaceae, Asteraceae etc., with a benzoylated c-pyrone ring which is a part of the structure of flavonoid skeletons[3,4,5] It is recognised as a privileged structure and a useful template for the design of novel compounds with potential pharmacological interest, in the field of neurodegenerative[6,7], inflammatory[8,9], biocidal[10], immune-stimulatory[11], infectious diseases[12,13,14], as well as diabetes[15] and cancer[16,17,18,19,20,21]. In-depth apoptosis-related mechanisms of the most potent compound 15a, including cell cycle progression, induction of apoptosis, changes of mitochondrial membrane potential and the expression of apoptosis-related proteins, were explored
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