Synthesis and cdc25B inhibitory activity evaluation of chalcones

Mammalian cell communication and growth are regulated by protein phosphorylation, which is the product of a dynamic balance between the enzymatic activity of protein kinases and phosphatases. Cdc25 phosphatases are important members of the dual-specificity protein phosphatases (DSPases). They control cell cycle progression by activating cyclindependent serine/threonine protein kinases (Cdks) [1] that are responsible for the progression of eukaryotic cells through the cell cycle. The overexpression of cdc25 phosphatases is frequently associated with a wide variety of cancers. Cdc25B is one of the members of the cdc25 phosphatases and appears to be essential in the G2/M phase transition in human cells [2]. Cdc25B is a suitable target for drug intervention, since it has been shown to be an oncogene when overexpressed, showing up in increased levels in several human breast cancers [3], and cdc25B shows more specificity than other cdc25 phosphatases. Inhibition of cdc25B could prove therapeutically useful as a treatment for cancer [4]. Recently, the structure of the catalytic domains of cdc25B has been solved by X-ray crystallography [5], and a number of small-molecule inhibitors of cdc25B have been developed, such as EK6136 [6], tetrahydroisoquinolines [7], pyrazole derivatives [8], vitamin K analogues [9], adociaquinone B and naphthoquinone derivatives [10, 11], etc. Efforts are currently under way to synthesize specific smallmolecule cdc25B inhibitors that might have anticancer properties. Chalcones are naturally occurring flavonoids composed of two aromatic rings connected by a three-carbon unit forming an – unsaturated carbonyl group. They are pharmacologically relevant because of their ability to exert antioxidant, anticarcinogenic, antibacterial, and anti-inflammatory activities, etc. [12–14]. In light of their extremely high values, chalcones have become a hot topic for research and development. Although there has been much study of the inhibitory effects of flavonoids on cdc25 phosphatases [15–17] and the inhibitory effects of chalcones on proliferation of human malignant tumor cells [18, 19], far less known are the actions of chalcones on cdc25B [20]. This is important, since the structure of chalcone is more flexible so that it can enhance the binding between compounds and enzyme or make the binding much more easier. The aim of the present study, therefore, was to probe a small compound library for potential inhibitory structures and study the structure–activity relationship so as to guide further design of chalcone analogs with more potent activity. In this work, sixty-five compounds were synthesized and were evaluated for in vitro inhibitory activity against cdc25B at 20 g/mL inhibitor concentration with 3-O-methylfluorescein phosphate (OMFP) as a substrate using a previously described procedure [21]. Sodium vanadate was taken as a control (IC50, 9.821 0.838 mol/L). The results are summarized in Table 1. The results demonstrated that thirteen compounds inhibited the catalytic activity of cdc25B by more than 50%. Among them, two compounds (compounds 25 and 45) revealed a significant potency with more than 90% inhibition at the same concentration. However, the natural compounds 14 [22] and 20 [23] have almost no activity.