Synthesis of Bisphenol Neolignans Inspired by Honokiol as Antiproliferative Agents

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.

Keywords: Suzuki–Miyaura cross-coupling; antitumor activity; apoptosis; bisphenol neolignans; honokiol; polyphenols.

Figure 1

Chemical structures of magnolol (1) and honokiol (2).

Scheme 1

Synthesis of honokiol derivatives 3–9.

Scheme 2

Synthesis of bisphenol neolignans 12a-c. (a) These conditions were employed to obtain 11a and 11b; (b) these conditions were employed to obtain 11c.

Scheme 3

Synthesis of bisphenol neolignans 13a-c, 14a-c, and 15a.

Figure 2

GI50 values (µM) of bisphenol neolignans 2–9, 12a-c, 13a-c, 14a-c, and 15a and of the reference compound 5-fluorouracil (5-FU) on HCT-116, HT-29, and PC3 cell lines after an incubation time of 72 h. The results shown are means ± SD of four experiments.

Figure 3

Flow cytometry: (a) Typical images of cells analyzed by flow cytometry (Amnis FlowsSigh). Each cell (event) is visible in a bright field and stained by annexin-V positive, propidium iodide positive, and double positive cells; Flow cytometric dot plot of specific cell populations in HCT-116 (b) and PC3 (c) cell lines in the presence of 15a: live (double annexin/PI negative), necrosis (annexin negative and PI positive), early apoptosis (annexin positive), and late apoptosis (double annexin/PI positive).