Elsevier

Bioorganic & Medicinal Chemistry

Volume 25, Issue 22, 15 November 2017, Pages 6115-6125
Bioorganic & Medicinal Chemistry

Synthesis and cytotoxic activities of goniothalamins and derivatives

https://doi.org/10.1016/j.bmc.2017.02.004Get rights and content

Abstract

Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance.

Introduction

In the past, the natural product (R)-(+)-goniothalamin and its derivatives were shown to display biological activity against a broad range of cell lines,1, 2, 3, 4, 5 bacteria6 and fungi.6, 7 Goniothalamin can be isolated from plants of the genus of Goniothalamus, which grow in tropic and subtropic areas of Asia and Oceania.8 In 1967 Hlubucek et al. isolated goniothalamin for the first time from Cryptocarya caloneura and determined the stereogenic centre to be (S)-configured.9 This was revealed in 1979, when Meyer elucidated the structure of natural occurring goniothalamin as (R)-configured by the synthesis of both enantiomers.10

Goniothalamin, (R)-1, and its derivatives have an α,β-unsaturated δ-lactone as a central element, which can be used as a Michael-acceptor system with corresponding nucleophiles. Furthermore it seems, that the vinylic double bond and the configuration of the stereogenic centre in the lactone is essential for its cytotoxicity (Fig. 1).

In addition to the naturally-occurring (R)-(+)-goniothalamin (1), Fátima et al. showed that the (S)-enantiomer [(S)-1] and the two derivatives, (S,E)-6-(2-cyclohexylvinyl)-5,6-dihydro-2H-pyran-2-one [(S)-2] and (S,E)-6-(4-methoxystyryl)-5,6-dihydro-2H-pyran-2-one [(S)-3], have a higher potential towards the inhibition of kidney cell proliferation in comparison to the natural goniothalamin (R)-1, with IC50-values in the micromolar range (Fig. 2).1, 2, 3, 4, 5 They could also show, that the fully hydrogenated derivatives (R)-6-phenethyltetrahydro-2H-pyran-2-one and (S)-6-phenethyltetrahydro-2H-pyran-2-one have no cytotoxic effect.1

Further biological studies were reported by Wach et al. in 2010: They showed that naturally occurring (R)-goniothalamin [(R)-1] can inhibit the nucleocytoplasmatic transport.11 In 2013 Bruder et al. synthesized new goniothalamin derivatives, with an additional methyl groups at the now quaternary stereogenic centre of γ- and δ-lactones and substituents at the phenyl group. No increase in anti-proliferative activity of (E)-6-methyl-6-styryl-5,6-dihydro-2H-pyran-2-one and (E)-5-methyl-5-styrylfuran-2(5H)-one relative to natural product (R)-1 was observed. By adding a trifluoromethyl groups to the phenyl group of the methylated compounds, they could improve biological activity.12 Pilli et al. synthesized 29 novel goniothalamin analogues and reported that aza-analogues and γ-pyrones had no increased antiproliferative activity, while tri- and tetra-methoxylated goniothalamin derivatives showed a promising increase in cytotoxicity.13 All in all goniothalamin and its derivatives show a wide variety of biological effects, e.g., anti-inflammatory,14 anti-nociceptive14 anti-tumour activity15 as well as plant growth inhibition.15, 16

Here we would like to present our enantioselective synthetic route towards goniothalamin and derivatives. In addition, the corresponding results of cytotoxicity tests of these compounds on human lung adenocarcinoma cell line A549, human breast adenocarcinoma cell line MCF-7 as well as on the triple negative human breast cancer cell line HBL-100 demonstrate a first hint for a structure-activity relationship. With these cytotoxicity tests, we want to elucidate, which structural elements of the vinyl-lactone are essential for biological activity. Furthermore, we also performed assays with the Saccharomyces cerevisiae multidrug exporter Pdr5. Pdr5 is a functional homologue of Cdr1, an important drug efflux pump of the clinical relevant fungi Candida albicans. Consequently, the development of new inhibitors against these multidrug exporter proteins plays an important role in our daily fight against resistance fungi. Therefore, we analyzed goniothalamin derivatives with respect to their inhibitory capacity against Pdr5.

Section snippets

Synthesis of cyclopropane derivatives

To show the importance of different structural elements of goniothalamin, we decided to synthesize different derivatives and demonstrate the influence of the vinylic double bond on the cytotoxicity of the compound; more specifically, we synthesized cyclopropane derivatives 4 with the cyclopropyl unit instead of the vinylic double bond.

Synthesis of goniothalamin derivatives 4 was performed starting from cyclopropyl alcohol 5, which can be synthesized from corresponding cinnamic alcohol using a

Conclusion

Comparing the cytotoxicity results the following three conclusions can be drawn:

First, the configuration of the stereogenic centre plays an important role for cytotoxicity. Only the (R)-configured goniothalamins with the vinylic double bond demonstrated cytotoxicity. The (R)-configuration is in accordance to natural goniothalamin (R)-1. However, looking at the inhibition of the multidrug exporter Pdr5, no pronounced configurational preference was observed, while the substitution pattern

General procedures

Unless specified, the reactions were carried out by standard Schlenk-technique under dry Ar/N2 and magnetic stirring. Glassware was oven-dried at 120 °C overnight. Solvents were dried and purified by conventional methods prior to use; tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone. Solvents for chromatography (petroleum ether, ethyl acetate) were distilled prior to use. Column and flash column chromatography were performed on silica gel 60, 0.040–0.063 mm (230–400 mesh). TLC

Acknowledgments

We gratefully acknowledge the Studienstiftung des deutschen Volkes (Scholarship to A. W.), the AiF (‘ZIM Kooperationsprojekt’ KF3279X01AJ3), the Deutsche Forschungsgemeinschaft, the Heinrich-Heine-Universität Düsseldorf, and the Forschungszentrum Jülich GmbH for their generous support of our project. The PhD training of J.S. and A.K. is financed by the graduate program in Pharmacology and Experimental Therapeutics at the University of Cologne which is financially and scientifically supported by

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