Abstract
Honokiol (2) is a natural bisphenol neolignan showing a variety of biological properties, including antitumor activity. Some studies pointed out 2 as a potential anticancer agent in view of its antiproliferative and pro-apoptotic activity towards tumor cells. As a further contribution to these studies, we report here the synthesis of a small library of bisphenol neolignans inspired by honokiol and the evaluation of their antiproliferative activity. The natural lead was hence subjected to simple chemical modifications to obtain the derivatives 3–9; further neolignans (12a-c, 13a-c, 14a-c, and 15a) were synthesized employing the Suzuki–Miyaura reaction, thus obtaining bisphenols with a substitution pattern different from honokiol. These compounds and the natural lead were subjected to antiproliferative assay towards HCT-116, HT-29, and PC3 tumor cell lines. Six of the neolignans show GI50 values lower than those of 2 towards all cell lines. Compounds 14a, 14c, and 15a are the most effective antiproliferative agents, with GI50 in the range of 3.6–19.1 µM, in some cases it is lower than those of the anticancer drug 5-fluorouracil. Flow cytometry experiments performed on these neolignans showed that the inhibition of proliferation is mainly due to an apoptotic process. These results indicate that the structural modification of honokiol may open the way to obtaining antitumor neolignans more potent than the natural lead.
Highlights
The biaryl skeleton is relatively common among natural products and this structural feature is distinctive of bisphenol neolignans, a group of polyphenols belonging to the neolignan family [1].These compounds are biosynthesized through oxidative coupling of phenoxy radicals generated by enzymes such as laccase, peroxidase, or a cytochrome P450 [2]
On the basis of the above-cited biological properties of the natural lead 2, we planned to synthesize a small library of honokiol-inspired bisphenol neolignans
A first group of honokiol analogues was obtained through simple modifications of 2, as depicted in Scheme 1
Summary
The biaryl skeleton is relatively common among natural products and this structural feature is distinctive of bisphenol neolignans, a group of polyphenols belonging to the neolignan family [1].These compounds are biosynthesized through oxidative coupling of phenoxy radicals generated by enzymes such as laccase, peroxidase, or a cytochrome P450 [2]. The biaryl skeleton is relatively common among natural products and this structural feature is distinctive of bisphenol neolignans, a group of polyphenols belonging to the neolignan family [1]. (mainly M. officinalis) have been employed for centuries in traditional Chinese and Japanese medicine to treat many diseases, including anxiety, allergy, or gastrointestinal disorders [3,4]. These extracts have shown to possess promising biological activities, including anti-inflammatory, antioxidant, antiviral, anti-depressant, and anti-platelet activity [4,5].
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