Original article
Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs

https://doi.org/10.1016/j.ejmech.2015.01.007Get rights and content

Highlights

  • Four natural chalcones bearing prenyl or geranyl groups were synthesized.

  • Eleven 3′ or/and 5′-prenylated/geranylated chalcones analogs were prepared.

  • 5′-prenylation/geranylation of the chalcones enhanced the cytotoxicy 7–10 folds.

  • These chalcone derivatives inhibited K562' proliferation by inducing apoptosis.

Abstract

Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by 1H NMR, 13C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5′-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis.

Graphical abstract

A series of prenyl and geranyl substituted chalcone natural products and their derivatives were synthesized. The anti-cancer activity evaluation results revealed these chalcone derivatives inhibit K562 proliferation by inducing apoptosis.

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Introduction

Chalcones containing prenyl or geranyl groups are an abundant subclass of flavonoids which are widely found in nature and display a variety of biological and pharmacological activities. Isobavachalcone (1c), first isolated from Psoralea corylifolia [1], showed antibacterial, antifungal, anticancer, anti-reverse transcriptase, antitubercular, and antioxidant activities [2], [3], [4]. Bavachalcone (1a), also isolated from soraleaorylifolia [1], [5], was shown to display a significant inhibitory effect on baculovirus-expressed BACE-1 in vitro [6] as well as osteoclast differentiation [7]. These natural chalcones also exhibit extremely high α-glucosidase inhibitory activity [8]. Xanthoangelol (1b), isolated from fresh roots of Angelica keiskei [9], exhibits antibacterial activity against Gram-Positive pathogenic bacteria [10], antitumor-promoting activity and cytotoxicity against neuroblastoma cells, which induced apoptotic cell death via the mitochondrial pathway and had no cytotoxicity against normal cells [11]. The newly discovered compound 1d, 2′, 4′, 4-trihydroxy- 5-geranyl chalcone, coined here as isoxanthoangelol, was isolated from the leaves of Artocarpus communis, and reported to possess anticancer activity in SW 872 human liposarcoma cells (Fig. 1) [12].

Due to their structural uniqueness and potent bioactivity, the synthesis of prenylated and geranylated chalcone natural products has attracted much attention in recent years. In 2010, Jung reported the first total synthesis of 1b with a total yield of 16.8% starting from 4-dihydroxyacetophenone (1) [13]. Sugamoto subsequently finished the total synthesis of 1a, 1b and 1c with 12.4%, 28.1% and 17.2% overall yield respectively [14]. All of these syntheses used O-alkylation followed by Claisen rearrangement as the key steps to introduce the prenyl or geranyl groups. However, poor regioselectivity of the rearrangement limited their further use. Recently, McGlinchey applied iodination and Stille coupling to the synthesis of isobavachalocone. But the overall efficiency was low due to poor regiochemical control for the iodination as well as the low yield for the Stille coupling [15]. The 3′, 5′-diprenylated chalcone Medicagenin (2a) was isolated from the roots of Crotalaria medicagenia DC [16] and synthesized later by Narender [17] with a poor regioselectivity. However, no work has been reported on the synthesis and biological activity evaluation of other digeranylated chalcones, including 2b and analogs 2c and 2d.

As part of our ongoing program on the synthesis of flavonoid and chalcone natural products, we have recently reported a regioselective iodination of flavonoids by NIS under neutral conditions [18], regioselective iodinations of chalcone derivatives using this protocol and the total synthesis of the aforementioned chalcone natural products by Suzuki coupling of the iodinated intermediates as the key step [19], [20]. In this paper, we would like to report in details the synthesis and anticancer activity evaluation of the 3′ and/or 5′ prenylated/geranylated chalcone natural products (1ad, 2a) and their derivatives (2bd, 3340) as well as the likely molecular mechanism of their cytotoxic activity.

Section snippets

Chemistry

As shown in Scheme 1, iodide 3 was readily synthesized from the bis-MOM intermediate 2 by iodination of 1 with NIS in DMF [16]. Base promoted condensation of 3 with aldehyde 4 afforded the iodo precursor 5 which was converted into 6 and 7 by PdCl2(dppf) catalyzed and microwave-assisted coupling reaction with the corresponding boronic acid pinacol esters in good yields. Removal of the MOM protecting groups finished the first total synthesis of isoxanthoangelol (1d) in 36% overall yield and the

Results and discussion

The in vitro antitumor activities of the newly synthesized prenyl and geranyl substituted chalcone natural products and their derivatives on human tumor cell K562 were evaluated by MTT assay with Camptothecin as the positive control.

As can be seen from the data in Table 1, that 5′-mono-substitution could significantly improve chalcone's cytotoxicy, as the 5′-prenylated chalcone Bavachalcone (1a) and 5′-geranylated chalcone Isoxanthoangelol (1d) exhibited the inhibitory potency against K562 at

Conclusions

In summary, the first total synthesis of isoxanthoangelol (1d) was accomplished in 5 steps and 36% overall yield. The improved synthesis of bavachalcone (1a), xanthoangelol (1b) and isobavachalcone (1c) as well as the preparation of a series of novel 3′ or/and 5′ prenylated/geranylated chalcone derivatives were accomplished. The anticancer activity of the 16 newly synthesized chalcone derivatives against human tumor cell line K562 were evaluated and the test result illustrated that the

Chemistry

All chemicals (reagent grade) used were purchased from Sigma-Aldrich (U.S.A) and Aladdin-Reagent Co., Ltd (China). The solvents for reaction were distilled over Na (for toluene and THF) or CaH2 (for CH2Cl2) under a nitrogen atmosphere. All reactions were carried out in oven-dried glassware under an inert atmosphere (nitrogen or argon). Microwave reaction was carried out in Biotage Initiator made in Sweden. TLC was run on the silica gel coated aluminum sheets (Silica Gel 60GF254, E. Merck,

Acknowledgments

The authors sincerely thank the financial support from National Natural Science Foundation of China (21202118, 31301142), International Science & Technology Cooperation Program of China (2013DFA31160) and the Ministry of Education Changjiang Scholars and Innovative Research Team Development Plan (IRT1166).

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