Abstract
A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.
Highlights
Chemical modification of bioactive components of medicinal herbs is one of the most common approaches in drug discovery for new drugs and improved therapeutic properties
Little attention has been paid to the cytotoxicity and DNA binding affinity studies of 4-MU, which belongs to the same class of coplanar coumarin as novobiocin [10]
The synthesis of 7-hydroxy-4methylcoumarin 2 was carried out according to our previous work [21], which included the condensation of phenols with ethyl acetoacetate in the presence of the catalysis sodium bisulfate
Summary
Chemical modification of bioactive components of medicinal herbs is one of the most common approaches in drug discovery for new drugs and improved therapeutic properties. Coumarins are an important class of compounds obtained from nature and synthetic origin that possess diverse pharmacological and biological activities such as antitumor [1], anti-inflammatory [2], anticoagulant [3], anti-HIV [4], herbicidal [5] and fungicidal [6] activities. Novobiocin, a member of amino-4-hydroxycoumarin family, has been shown to possess anticancer activity, owing to its amide side chain, the coumarin ring and the sugar moiety [9]. Most DNA binding compounds containing a linear or angular planar chromophore with apolyaromatic ring can influence the structures and physiological functions of DNA [11]. Generally the DNA binding compounds should carry one or two flexible basic side chains on chromophore [12]. The flexible basic side chains are highly influential in directing the thermodynamic-binding mechanism, geometry of the ligand-DNA complex and sequence selectivities [13]
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