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Article

Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation

by
Emily K. Paulin
1,2,
Euphemia Leung
3,4,
Lisa I. Pilkington
1 and
David Barker
1,2,*
1
School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand
2
The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington 6012, New Zealand
3
Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand
4
Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(2), 1167; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021167
Submission received: 7 December 2022 / Revised: 22 December 2022 / Accepted: 4 January 2023 / Published: 6 January 2023
(This article belongs to the Topic Antitumor Activity of Natural Products and Related Compounds)
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Abstract

:
Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9′ position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9′-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9′ derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9′-hydroxymethyl lead compound.

1. Introduction

Lignans are a large natural product class of structurally and functionally diverse phenylpropanoids, isolated from over 70 known families of plants worldwide [1,2,3,4]. The lignan framework is derived from the oxidative dimerisation of two phenylpropane (C-6–C-3) moieties, which produces a linkage between each monomer’s propyl side chains at the respective C-8 carbons [1,5].
Arctigenin is a natural product belonging to the dibenzylbutyrolactone subclass of lignans (Figure 1). These structures comprise a γ-lactone core, with dibenzyl substitution at the C-8 and C-8’ positions in an anti-relationship [6,7]. Arctigenin possesses a range of biological activities and consequently has been well-studied to determine structure-activity relationships of its derivatives [6,7,8,9,10,11,12]. Results from previous studies have confirmed the lignan’s biological activities, with arctigenin analogues having cytotoxic, anti-tumour and hypoglycaemic activities, amongst others [10,12,13,14]. Many of these derivatives have explored modifications of the aromatic rings, and to a slightly lesser extent the benzylic positions, [9,11,13,15,16], but there is a large underrepresentation of lactone ring modifications.
To date, only one synthetic derivative of arctigenin with C-9′ modification has been reported—a compound containing a methylenehydroxy group at C-5 in the lactone ring (C-9′ according to lignan nomenclature, Figure 1 right) [17,18]. This compound showed the induction of apoptosis in Jurkat T cells with only 2% necrosis. This derivative was accessed using an acyl-Claisen rearrangement as the key step to establish the necessary trans relationship between C-8 and C-8’ groups. The prolific activities of arctigenin and lack of SAR information at the C-9′ position inspired this work to synthesise additional C-9′ analogues. Herein, we report the synthesis of 15 arctigenin derivatives with different C-9′ substitution, and their anti-proliferative activities.

2. Results and Discussion

2.1. Retrosynthetic Analysis of C-9′ Arctigenin Analogues

The proposed pathway to access the targeted arctigenin analogues also exploited an acyl-Claisen rearrangement [17] to introduce the correct relative stereochemistry between benzyl groups in the morpholine pentenamide 1 and converged two parallel pathways (Scheme 1). Cyclisation of the rearrangement product was envisaged to establish the core DBL lactone framework and included the C-9′ substitution of a methylenehydroxy group, from which derivatisations could be prepared. The acyl-Claisen precursors, an acid chloride 2 and allylic morpholine 3, could be prepared from vanillin 4 and 4-allyl-1,2-dimethoxybenzene 5, respectively, through two separate routes.

2.2. Synthesis of Acid Chloride 2

Acid chloride 2 was prepared when required from the more stable carboxylic acid 6. Synthesis of 6 began from vanillin 4, which was subjected to a Wittig olefination with (carbethoxymethylene)triphenylphosphorane, following literature methods [17] to give α,β-unsaturated ethyl ester 7 in 80% yield (E:Z, 92:8). The newly installed alkene was reduced by catalytic hydrogenation to give saturated ester 8 in quantitative yield (Scheme 2). With the saturated ester 8 in hand, the phenol substituent was protected as the benzyl ether to give 9 in 93% yield. Hydrolysis of the ester 9 gave carboxylic acid 6 in 92% yield and the resulting acid chloride was prepared in situ at the time of the successive step due to its instability.

2.3. Synthesis of Allylic Morpholine 3

To obtain allylic morpholine 3, 4-allyl-1,2-dimethoxybenzene 5 was first dehydroxylated, under Upjohn conditions [19], to give diol 10 in 94% yield (Scheme 3). The newly formed diol moiety then underwent oxidative cleavage using NaIO4 [17], to afford aldehyde 11 in 97% yield, which was used immediately, due to its tendency to degrade even stored at low temperatures. Thus, 11 underwent a Horner-Wadsworth-Emmons (HWE) reaction, forming the respective (E)-α,β-unsaturated ethyl ester 12 in 73% yield [20,21,22]. During repeated syntheses of α,β-unsaturated ester 12, the E-selectivity of the Horner-Wadsworth-Emmons reaction was found to vary with the formation of both the Z-isomer and a third regioisomer, which was determined to be a β,γ-unsaturated ester 13 (Scheme 3). Separation of the desired E-isomer 12 on AgNO3-treated silica was possible but poor, leading to diminished yields.

2.4. Prevention of Isomeric Esters

Only E-isomer E-12 was required for further steps, therefore, in order to prevent double bond migration to form 13, different conditions were trialled for the formation of allylic ester 12. While the mechanism of rearrangement was not confirmed, it was proposed to be base-mediated, through abstraction of the γ-proton after formation of the initial α,β-unsaturated product (Scheme 3), with the resulting β,γ-unsaturated product 13 stabilised by increased conjugation. As a result, different bases were screened. The migrated isomer was observed to a lesser extent under kinetic control or with the use of hindered bases, such as DBU under Masamune-Roush conditions [23], but unfortunately, these reactions still had poor E/Z stereocontrol. After reports of MeMgBr use to suppress isomerisation in PhCH2CHO aldehydes, this was applied as a base in the HWE reaction between triethylphosphonoacetate and aldehyde 11 [24]. As a result, neither the migrated species 13 nor Z-isomer Z-12 were observed. On a larger scale, good selectivity was maintained (9:1 E:Z), but unfortunately, the yield was poor (10%), so the exploration of other methods was resumed.

2.5. Grubbs Cross Metathesis Pathway; Revised Route to 3

An alternative route which did not involve a HWE reaction was then developed by implementing a cross metathesis [25] approach between 4-allyl-1,2-dimethoxybenzene 5 and ethyl acrylate. Using Grubb’s second-generation catalyst at a loading of 5 mol-% and three equivalents of ethyl acrylate, full conversion to the E product E-12 took place in 91% yield. No migrated product 13 was observed, allowing large scale synthesis of ester E-12.
Ester E-12 was then fully reduced to primary allylic alcohol 14 using DIBAL-H (Scheme 4). The final step towards allylic morpholine 3 involved substitution of the hydroxyl group in 14 for a morpholine moiety. The reaction was attempted using various strategies, including via mesylation, tosylation and bromination with all giving the desired product 3, but in poor yields.
In an alternate approach, acetate 15 was then synthesised from alcohol 14, then subjected to Tsuji-Trost allylation conditions, using palladium tetrakis Pd(PPh3)4 and morpholine. With the possibility of two regioisomers of the allylic amine product, thermodynamic control was implemented to ensure the desired linear isomer was obtained over the possible kinetic branched product [26]. Over two steps from the allylic alcohol 14, the desired allylic morpholine 3 was achieved in 83% yield as solely the E-isomer, linear product (Scheme 4).

2.6. Synthesis of 9’-CH2OH Lactones

With 3 and 6 prepared, acid 6 was then converted to acid chloride 2 in situ using oxalyl chloride, before undergoing a TiCl4.2THF induced acyl-Claisen rearrangement [17,27] with (E)-allylic morpholine 3. One equivalent of TiCl4.2THF was required, as we have previously shown acyl-Claisen rearrangements with aromatic substituents require stochiometric amounts of Lewis acid to occur [27]. The rearrangement successfully took place to give racemic morpholine amide 1 in 85% yield as a single syn-diastereomer. Dihydroxylation, again under Upjohn conditions, cyclised amide 1 in situ to γ-lactone 16 in 88% yield (Scheme 5). The cyclisation proceeds through a diol intermediate, from which anti-17 spontaneously formed lactone 16. Syn-diol 17 was also formed in 12% yield and did not undergo cyclisation. This allowed syn-17 to be isolated and treated with 2 M HCl to give the epimeric lactone 18 with a trans,cis relationship between the C-8, C-8’ and C-9′ stereocentres. Under both sets of conditions, the respective diastereomer (16 or 18) was afforded as the sole product. The benzyl ether in each diastereomer was deprotected to their respective phenol, in 56% yield as trans,cis isomer 19 and trans,trans isomer 20 in quantitative yields (Scheme 5).

2.7. Synthesis of Lactone Derivatives

With lactone 16 successfully synthesised, a range of C-9′ functionalised derivatives were targeted to explore the effects of modifications at this position on the anti-proliferative activity.

2.7.1. Ester Derivatives

A series of ester derivatives was completed to add prodrug-like groups, capable of being cleaved by cellular esterases [28]. Differing ester groups were installed using the addition of acid chlorides to lactone 16 with Et3N and catalytic DMAP. Differing chain lengths and aromaticity were accessed with the synthesis of acetate 21, propionate 22, and benzoate 23 esters (Scheme 6). An additional benzoate ester 24 was synthesised from isomer 19, in 48% yield, to provide an example of the epimeric trans,cis form. Following derivatisation of the 9’-CH2OH functionality, the benzylic ether at C-4 was removed via catalytic hydrogenation to give the free phenol, a directly comparable analogue of arctigenin. The synthesis of 21–24 was achieved in yields ranging from 72–88%. Deprotection of the benzyl ether in all the ester analogues gave C-4 phenols 25–27, in yields of 64% to quantitative (Scheme 6).

2.7.2. Azido Derivatives

In addition to the obtained ester derivatives, it was decided to install a triazole scaffold due to its presence in clinically used drugs, with a range of pharmacological activities and ability to enhance solubility [29,30,31]. As a preliminary example of triazole derivatised arctigenin, the simple 4-phenyl-1H-1,2,3-triazole moiety was accessed through a copper-catalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click reaction between azide-containing arctigenin analogue 29 and phenylacetylene.
Azide 29 was afforded through a two-step approach of mesylation and subsequent displacement using sodium azide, affording azide 29 in 78% yield over two steps (Scheme 7). This process also saw formation of a minor alkyl chloride side product 30 through halide displacement.
The reaction of azide 29 and phenylacetylene was achieved using sodium ascorbate and copper sulfate pentahydrate in acetonitrile and after four days obtained the 1,4-disubstituted triazole 32 in 74% yield (Scheme 7).
Chloride 30 was stable to catalytic hydrogenation conditions and the benzyl ether removed cleanly through hydrogenolysis to give 33 in 29% yield. However, hydrogenation of triazole 32 was found to be surprisingly difficult and the desired phenol could not be obtained even after using a variety of conditions.

2.8. Anti-Proliferative Activity

Following the synthesis of the arctigenin derivatives, their anti-proliferative activities were evaluated against colorectal cancer HCT-116 and triple negative breast cancer MDA-MB-231 cell lines (Table 1). Arctigenin has previously been shown to affect the growth of MDA-MB-231 [32] whilst the HCT-116 has been used for the anti-proliferative assessment of polyphenolic natural products [33,34]. All of the compounds showed improved activity in the HCT-116 cell line over MDA-MB-231 cells. Five of the fifteen compounds had better activity than the previously prepared hydroxylmethylene derivative 16 in the MDA-MB-231 cell line, and 10 out of the 15 compounds had better activity than that reported for arctigenin itself [32]. It was found that compounds with aromatic benzylic ethers tended to outperform their phenol counterparts, and trans,trans stereochemistry between C-8, C-8’ and C-9′ was favourable over a trans,cis relationship. The most potent four compounds, based upon their ability to inhibit cell growth at 10 µM, were the same across both cell lines; 24, 29, 32, and 33, and their IC50 values were determined. All of the tested compounds, 24, 29, 32 and 33 produced similar inhibition–with mean IC50 values ranging between 5.79–7.45 µM (MDA-MB-231) and 3.27–6.10 µM (HCT-116) (Table 2).

3. Materials and Methods

3.1. Synthesis

General experimental details: All reactions were carried out under an inert atmosphere using distilled anhydrous solvents unless otherwise specified. Triethylamine and diisopropylethylamine were each distilled and stored over activated 4 Å Molecular Sieves. All NMR spectra were recorded on a Bruker Avance DRX 400 MHZ spectrometer at ambient temperature. Chemical shifts are reported relative to the solvent peak of CDCl3 (δ 7.26 for 1H and δ 77.16 for 13C) or DMSO (δ 2.50 for 1H and δ 39.52 for 13C). 1H NMR data are reported as position (δ), relative integral, multiplicity (s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of triplets; dq, doublet of quartets; t, triplet; td, triplet of doublets; q, quartet; m, multiplet), coupling constant (J, Hz), and the assignment of the atom. Proton-decoupled 13C NMR data are reported as position (δ) and assignment of the atom. NMR assignments were performed using HMBC, COSY and HSQC, experiments. 1H and 13C NMR spectra for all precursor and final compounds (Figures S1–S45) are found in the supplementary material. The numbering of arctigenin analogues was done according to lignan nomenclature, with the two C-6-C-3 units numbered 1–9 and 1’–9’ [18]. All melting points for solid compounds are given in degrees Celsius (°C), were measured using a Reicher-Kofler block, and are uncorrected. A Perkin-Elmer Spectrum 1000 series Fourier Transform Infrared ATR spectrometer was used to record infrared spectra. Absorption maxima are expressed in wavenumbers (cm−1). High-resolution mass spectroscopy (HRMS) was carried out by electrospray ionisation (ESI+) on a MicroTOF-Q II mass spectrometer. Fétizon’s reagent was prepared following a literature procedure [35]. Unless noted, chemical reagents were used as purchased. General procedures, synthetic experimental methods, and full characterisation data (including copies of NMR spectra for all synthesised final compounds) can be found in the Supplementary Materials.

3.2. Cell Proliferation Assays

The synthesised arctigenin derivatives were measured for anti-proliferative activity against colorectal cancer HCT-116 and triple negative breast cancer MDA-MB-231 cell lines using 3H-thymidine incorporation assays. Cell lines were purchased from the American Type Culture Collection (ATCC). The anti-proliferative assays were conducted according to our previously reported methods. [36,37,38]. In short, cells were seeded in 96 well plates with 3000 cells per well and incubated with 10 µM of arctigenin-derived compounds for three days. An amount of 0.04 μCi of 3H-thymidine was added per well and incubated for 5 h before cells were harvested and counted. All experiments were performed in duplicate wells on separate plates with three repeats. The percentage of cells which showed incorporation of 3H-thymidine into the DNA relative to the control samples directly measured the cell proliferation. Two known previously active compounds were used as positive controls [39], alongside a negative control, with no compounded added.

4. Conclusions

In this study, fifteen novel C-9′ derivatives of arctigenin with C-9′ substitution were successfully synthesised, and analysed for their anti-proliferative activities, for the first time. This study demonstrated the use of acyl-Claisen rearrangement as an effective method to access a dibenzylbutyrolactone framework as a single trans diastereomer between C-8 and C-8’ and to provide C-9′ analogues with a trans,trans C-8, C-8’, C-9′ configuration. The benefits of this divergent strategy are evident through the preparation of these derivatives. Anti-proliferative testing of the synthesised compounds showed IC50 values as low as 3.27 µM in HCT-116 (compound 32) and 5.79 µM (compound 29) in MDA-MB-231 cancer cell lines, which were improved over the natural product, arcitgenin, itself. These results highlight that C-9′ substitution of dibenzylbutyrolactone lignans can improve the biological activity compared to the unsubstituted natural products. Furthermore, as the C-9′ is rarely substituted in other lignan natural products, this work suggests the potential that other classes of lignans could be similarly modified to increase their biological activity.

Supplementary Materials

The following supporting information can be downloaded at: https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/ijms24021167/s1. Synthetic procedures for all novel compounds, 1H and 13C NMR spectra for all precursor and final compounds (Figures S1–S45). References [17,40,41,42,43,44,45,46,47,48,49] are cited in supplementary materials.

Author Contributions

Conceptualization, D.B.; methodology, E.K.P., E.L., L.I.P. and D.B.; validation, E.K.P. and E.L.; investigation, E.K.P. and E.L.; resources, E.L., L.I.P. and D.B.; writing—original draft preparation, E.K.P.; writing—review and editing, E.K.P., L.I.P. and D.B.; supervision, D.B. and L.I.P.; project administration, L.I.P. and D.B.; funding acquisition, D.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data are contained within the article.

Acknowledgments

The authors would like to acknowledge financial support for this work from the University of Auckland (doctoral scholarship for E.K.P.).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Tsopmo, A.; Awah, F.M.; Kuete, V. 12—Lignans and stilbenes from african medicinal plants. In Medicinal Plant Research in Africa; Kuete, V., Ed.; Elsevier: Oxford, UK, 2013; pp. 435–478. [Google Scholar] [CrossRef]
  2. Barker, D. Lignans. Molecules 2019, 24, 1424. [Google Scholar] [CrossRef] [Green Version]
  3. Gordaliza, M.; Castro, M.A.; del Corral, J.M.; Feliciano, A.S. Antitumor Properties of Podophyllotoxin and Related Compounds. Curr. Pharm. Des. 2000, 6, 1811–1839. [Google Scholar] [CrossRef] [PubMed]
  4. Pan, J.-Y.; Chen, S.-L.; Yang, M.-H.; Wu, J.; Sinkkonen, J.; Zou, K. An Update on Lignans: Natural Products and Synthesis. Nat. Prod. Rep. 2009, 26, 1251–1292. [Google Scholar] [CrossRef] [PubMed]
  5. Haworth, R.D. The Chemistry of the Lignan Group of Natural Products. J. Chem. Soc. 1942, 448–456. [Google Scholar] [CrossRef]
  6. Solyomváry, A.; Boldizsar, I.; Beni, S. Dibenzylbutyrolactone Lignans—A Review of Their Structural Diversity, Biosynthesis, Occurrence, Identification and Importance. Mini-Rev. Med. Chem. 2017, 17, 1053–1074. [Google Scholar] [CrossRef] [PubMed]
  7. Srivastava, D. Arctigenin, a Plant Lignan with Tremendous Potential: A Review. Int. J. Curr. Res. 2017, 9, 6. [Google Scholar]
  8. Kamlage, S.; Sefkow, M.; Pool-Zobel, B.L.; Peter, M.G. A Short Synthesis of Biologically Active Lignan Analogues. Chem. Commun. 2001, 331–332. [Google Scholar] [CrossRef]
  9. Duan, S.; Huang, S.; Gong, J.; Shen, Y.; Zeng, L.; Feng, Y.; Ren, W.; Leng, Y.; Hu, Y. Design and Synthesis of Novel Arctigenin Analogues for the Amelioration of Metabolic Disorders. ACS Med. Chem. Lett. 2015, 6, 386–391. [Google Scholar] [CrossRef] [Green Version]
  10. Shen, S.; Zhuang, J.; Chen, Y.; Lei, M.; Chen, J.; Shen, X.; Hu, L. Synthesis and Biological Evaluation of Arctigenin Ester and Ether Derivatives as Activators of AMPK. Bioorg. Med. Chem. 2013, 21, 3882–3893. [Google Scholar] [CrossRef] [Green Version]
  11. Eich, E.; Pertz, H.; Kaloga, M.; Schulz, J.; Fesen, M.R.; Mazumder, A.; Pommier, Y. (−)-Arctigenin as a Lead Structure for Inhibitors of Human Immunodeficiency Virus Type-1 Integrase. J. Med. Chem. 1996, 39, 86–95. [Google Scholar] [CrossRef]
  12. Awale, S.; Kato, M.; Dibwe, D.F.; Li, F.; Miyoshi, C.; Esumi, H.; Kadota, S.; Tezuka, Y. Antiausterity Activity of Arctigenin Enantiomers: Importance of (2R,3R)-Absolute Configuration. Nat. Prod. Commun. 2014, 9, 79–82. [Google Scholar] [CrossRef] [Green Version]
  13. Kudou, N.; Taniguchi, A.; Sugimoto, K.; Matsuya, Y.; Kawasaki, M.; Toyooka, N.; Miyoshi, C.; Awale, S.; Dibwe, D.F.; Esumi, H.; et al. Synthesis and Antitumor Evaluation of Arctigenin Derivatives Based on Antiausterity Strategy. Eur. J. Med. Chem. 2013, 60, 76–88. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, L.; Zhao, F.; Liu, K. [Induction of apoptosis of the human leukemia cells by arctigenin and its mechanism of action]. Yao Xue Xue Bao 2008, 43, 542–547. [Google Scholar] [PubMed]
  15. Alizadeh, B.H.; Foroumadi, A.; Kobarfard, F.; Saeedi, M.; Shafiee, A. Synthesis of Novel Dibenzylbutyrolactones as Dimethylmatairesinol Analogues. J. Heterocycl. Chem. 2014, 52, 1693–1698. [Google Scholar] [CrossRef]
  16. Želazková, J. Total synthesis of arctigenin derivatives as potential anticancer agents. In Proceedings of the 15th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-15), Online, 1–30 November 2011; p. 9. [Google Scholar] [CrossRef]
  17. Davidson, S.J.; Pilkington, L.I.; Dempsey-Hibbert, N.C.; El-Mohtadi, M.; Tang, S.; Wainwright, T.; Whitehead, K.A.; Barker, D. Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans. Molecules 2018, 23, 3057. [Google Scholar] [CrossRef] [Green Version]
  18. Moss, G.P. Nomenclature of Lignans and Neolignans (IUPAC Recommendations 2000). Pure Appl. Chem. 2000, 72, 1493–1523. [Google Scholar] [CrossRef]
  19. VanRheenen, V.; Kelly, R.C.; Cha, D.Y. An Improved Catalytic OsO4 Oxidation of Olefins to Cis-1,2-Glycols Using Tertiary Amine Oxides as the Oxidant. Tetrahedron Lett. 1976, 17, 1973–1976. [Google Scholar] [CrossRef]
  20. Molnár, K.; Takács, L.; Kádár, M.; Faigl, F.; Kardos, Z. Z- and E-Selective Horner–Wadsworth–Emmons Reactions. Synth. Commun. 2017, 47, 1214–1224. [Google Scholar] [CrossRef]
  21. Carruthers, J.E.; Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis; Cambridge University Press: Cambridge, UK, 2004. [Google Scholar]
  22. Wadsworth, W.S.; Emmons, W.D. The Utility of Phosphonate Carbanions in Olefin Synthesis. J. Am. Chem. Soc. 1961, 83, 1733–1738. [Google Scholar] [CrossRef]
  23. Blanchette, M.A.; Choy, W.; Davis, J.T.; Essenfeld, A.P.; Masamune, S.; Roush, W.R.; Sakai, T. Horner-Wadsworth-Emmons Reaction: Use of Lithium Chloride and an Amine for Base-Sensitive Compounds. Tetrahedron Lett. 1984, 25, 2183–2186. [Google Scholar] [CrossRef]
  24. Claridge, T.D.W.; Davies, S.G.; Lee, J.A.; Nicholson, R.L.; Roberts, P.M.; Russell, A.J.; Smith, A.D.; Toms, S.M. Highly (E)-Selective Wadsworth−Emmons Reactions Promoted by Methylmagnesium Bromide. Org. Lett. 2008, 10, 5437–5440. [Google Scholar] [CrossRef]
  25. Ogba, O.M.; Warner, N.C.; O’Leary, D.J.; Grubbs, R.H. Recent Advances in Ruthenium-Based Olefin Metathesis. Chem. Soc. Rev. 2018, 47, 4510–4544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Dubovyk, I.; Watson, I.D.G.; Yudin, A.K. Achieving Control over the Branched/Linear Selectivity in Palladium-Catalyzed Allylic Amination. J. Org. Chem. 2013, 78, 1559–1575. [Google Scholar] [CrossRef]
  27. Barker, D.; Dickson, B.; Dittrich, N.; Rye, C.E. An Acyl-Claisen Approach to the Synthesis of Lignans and Substituted Pyrroles. Pure Appl. Chem. 2012, 84, 1557–1565. [Google Scholar] [CrossRef]
  28. Yang, Y.; Aloysius, H.; Inoyama, D.; Chen, Y.; Hu, L. Enzyme-Mediated Hydrolytic Activation of Prodrugs. Acta Pharm. Sin. B 2011, 1, 143–159. [Google Scholar] [CrossRef] [Green Version]
  29. Kharb, R.; Sharma, P.C.; Yar, M.S. Pharmacological Significance of Triazole Scaffold. J. Enzyme Inhib. Med. Chem. 2011, 26, 1–21. [Google Scholar] [CrossRef] [PubMed]
  30. Hein, J.E.; Fokin, V.V. Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) and beyond: New Reactivity of Copper(I) Acetylides. Chem. Soc. Rev. 2010, 39, 1302–1315. [Google Scholar] [CrossRef] [PubMed]
  31. Liang, L.; Astruc, D. The Copper(I)-Catalyzed Alkyne-Azide Cycloaddition (CuAAC) “Click” Reaction and Its Applications. An Overview. Coord. Chem. Rev. 2011, 255, 2933–2945. [Google Scholar] [CrossRef]
  32. Lou, C.; Zhu, Z.; Zhao, Y.; Zhu, R.; Zhao, H. Arctigenin, a Lignan from Arctium Lappa L., Inhibits Metastasis of Human Breast Cancer Cells through the Downregulation of MMP-2/-9 and Heparanase in MDA-MB-231 Cells. Oncol. Rep. 2017, 37, 179–184. [Google Scholar] [CrossRef]
  33. Paulin, E.K.; Leung, E.; Pilkington, L.I.; Barker, D. The enantioselective total syntheses of (+)-7-oxohinokinin, (+)-7-oxoarcitin, (+)-conicaol B and (−)-isopolygamain. Org. Biomol. Chem. 2022, 20, 4324–4330. [Google Scholar] [CrossRef]
  34. Lo, S.; Leung, E.; Fedrizzi, B.; Barker, D. Syntheses of mono-acylated luteolin derivatives, evaluation of their antiproliferative and radical scavenging activities and implications on their oral bioavailability. Sci. Rep. 2021, 11, 12595. [Google Scholar] [CrossRef]
  35. Kakis, F.J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. Mechanistic Studies Regarding the Oxidation of Alcohols by Silver Carbonate on Celite. J. Org. Chem. 1974, 39, 523–533. [Google Scholar] [CrossRef]
  36. Leung, E.; Kim, J.E.; Rewcastle, G.W.; Finlay, G.J.; Baguley, B.C. Comparison of the Effects of the PI3K/MTOR Inhibitors NVP-BEZ235 and GSK2126458 on Tamoxifen-Resistant Breast Cancer Cells. Cancer Biol. Ther. 2011, 11, 938–946. [Google Scholar] [CrossRef] [Green Version]
  37. Hung, J.M.; Arabshahi, H.J.; Leung, E.; Reynisson, R.; Barker, D. Synthesis and cytotoxicity of thieno[2,3-b]pyridine and furo[2,3-b]pyridine derivatives. Eur. J. Med. Chem. 2014, 86, 420–437. [Google Scholar] [CrossRef]
  38. Haverkate, N.A.; Leung, E.; Pilkington, L.I.; Barker, D. Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-b]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC. Pharmaceutics 2021, 13, 2020. [Google Scholar] [CrossRef] [PubMed]
  39. Rees, S.W.P.; Barker, D.; Pilkington, L.I.; Leung, E.; Reynisson, J. Development of 2-Morpholino-N-Hydroxybenzamides as Anti-Proliferative PC-PLC Inhibitors. Bioorg. Chem. 2021, 114, 105152. [Google Scholar] [CrossRef] [PubMed]
  40. Xia, Y.; Mo, Z.; Sun, L.; Zou, L.; Zhang, W.; Zhang, J.; Wang, L. First Total Synthesis of Quiquesetinerviusin A. J. Chem. Res. 2017, 41, 296–300. [Google Scholar] [CrossRef]
  41. Hattori, H.; Mitsunaga, T.; Clive, D.L.J. Synthesis of Phenolic Components of Grains of Paradise. Tetrahedron Lett. 2019, 60, 1989–1991. [Google Scholar] [CrossRef]
  42. Purushotham Reddy, S.; Chinnababu, B.; Venkateswarlu, Y. First Stereoselective and Concise Synthesis of Rhoiptelol C. Helv. Chim. Acta 2014, 97, 999–1003. [Google Scholar] [CrossRef]
  43. Mane, B.B.; Kumbhar, D.D.; Waghmode, S.B. Enantioselective Total Synthesis of Ligraminol D and Ligraminol E. Synlett 2019, 30, 2285–2289. [Google Scholar] [CrossRef]
  44. Kikuzaki, H.; Hara, S.; Kawai, Y.; Nakatani, N. Antioxidative Phenylpropanoids from Berries of Pimenta Dioica. Phytochemistry 1999, 52, 1307–1312. [Google Scholar] [CrossRef]
  45. Davies, S.G.; Goddard, E.C.; Roberts, P.M.; Russell, A.J.; Smith, A.D.; Thomson, J.E.; Withey, J.M. Strategies for the Construction of Morphinan Alkaloid AB-Rings: Regioselective Friedel-Crafts-Type Cyclisations of γ-Aryl-β-Benzoylamido Acids with Asymmetrically Substituted γ-Aryl Rings. Tetrahedron Asymmetry 2016, 27, 274–284. [Google Scholar] [CrossRef]
  46. Sun, R.; Song, W.; Ma, C.; Zhang, H.; Yu, X. Titanium(IV) Chloride-Mediated Stereoselective α-Alkylidenation to Efficiently Assemble Multisubstituted 1,3-Dienes. Adv. Synth. Catal. 2016, 358, 3977–3982. [Google Scholar] [CrossRef]
  47. Hryniewicka, A.; Misztalewska, I.; Czajkowska-Szczykowska, D.; Urbańczyk-Lipkowska, Z.; Morzycki, J.W.; Witkowski, S. New Olefin Metathesis Catalysts Bearing Polyether Clamp in N-Heterocyclic Carbenes Ligands. Tetrahedron 2014, 70, 6810–6816. [Google Scholar] [CrossRef]
  48. Parpal, F.; Pandolfi, E.; Heguaburu, V. (π-Allyl)Palladium Coupling of 2-(Tributylstannyl)cyclopent-2-enone for the Synthesis of Jasmonoid Analogs. Tetrahedron Lett. 2017, 58, 1965–1968. [Google Scholar] [CrossRef]
  49. Dittrich, N.; Pilkington, L.I.; Leung, E.; Barker, D. Synthesis of N-Benzyl-des-D-ring Lamellarin K via an Acyl-Claisen/Paal-Knorr Approach. Tetrahedron 2017, 73, 1881–1894. [Google Scholar] [CrossRef]
Ijms 24 01167 g001 550
Figure 1. Arctigenin (left) and racemic C-9′ methylenehydroxy analogue (right).
Figure 1. Arctigenin (left) and racemic C-9′ methylenehydroxy analogue (right).
Ijms 24 01167 g001
Ijms 24 01167 sch001 550
Scheme 1. Retrosynthetic approach to racemic C-9′ analogues.
Scheme 1. Retrosynthetic approach to racemic C-9′ analogues.
Ijms 24 01167 sch001
Ijms 24 01167 sch002 550
Scheme 2. Synthesis of acid 6. Reagents and conditions: (i) Ph3PCHCO2Et (1.1 equiv.), CH2Cl2, rt, 21 h, 7 80%; (ii) H2, Pd/C (10% w/w), EtOAc, rt, 20 h, 8 quant.; (iii) BnBr (3 equiv.), K2CO3 (3 equiv.), MeCN, 80 °C, 46 h, 9 93%; (iv) NaOH (4.5 equiv.), MeOH, rt, 2.5 h, 6 92%.
Scheme 2. Synthesis of acid 6. Reagents and conditions: (i) Ph3PCHCO2Et (1.1 equiv.), CH2Cl2, rt, 21 h, 7 80%; (ii) H2, Pd/C (10% w/w), EtOAc, rt, 20 h, 8 quant.; (iii) BnBr (3 equiv.), K2CO3 (3 equiv.), MeCN, 80 °C, 46 h, 9 93%; (iv) NaOH (4.5 equiv.), MeOH, rt, 2.5 h, 6 92%.
Ijms 24 01167 sch002
Ijms 24 01167 sch003 550
Scheme 3. Synthesis of allylic ester 12. Reagents and conditions: (i) OsO4 (2.5 mol-%), NMO (3 equiv.), t-BuOH/H2O (1:1), rt, 4 days, 10 94%; (ii) NaIO4 (1.2 equiv.), MeOH/H2O (3:1), rt, 3 days, 11 97%; (iii) (EtO)2POCH2CO2Et (1.5 equiv.), NaH (2 equiv.), THF, 0 °C to rt, 18 h, E-12, 39%, Z-12 2%, 13 7%.
Scheme 3. Synthesis of allylic ester 12. Reagents and conditions: (i) OsO4 (2.5 mol-%), NMO (3 equiv.), t-BuOH/H2O (1:1), rt, 4 days, 10 94%; (ii) NaIO4 (1.2 equiv.), MeOH/H2O (3:1), rt, 3 days, 11 97%; (iii) (EtO)2POCH2CO2Et (1.5 equiv.), NaH (2 equiv.), THF, 0 °C to rt, 18 h, E-12, 39%, Z-12 2%, 13 7%.
Ijms 24 01167 sch003
Ijms 24 01167 sch004 550
Scheme 4. Synthetic pathway to allylic morpholine 3 using cross metathesis approach. Reagents and conditions: (i) Ethyl acrylate (3 equiv.), Grubbs II (1.9 mol-%), CH2Cl2, rt, 24 h, 12 91%; (ii) DIBAL-H (2.9 equiv.), PhMe, −10 °C to rt, 20 h, 14 quant.; (iii) Ac2O (2.2 equiv.), Et3N (3 equiv.), DMAP (10 mol-%), CH2Cl2, 0 °C to rt, 25 h, 15; (iv) morpholine (1.9 equiv.), Pd(PPh3)4 (5 mol-%), THF, reflux, 5 days, 3 83% (two steps).
Scheme 4. Synthetic pathway to allylic morpholine 3 using cross metathesis approach. Reagents and conditions: (i) Ethyl acrylate (3 equiv.), Grubbs II (1.9 mol-%), CH2Cl2, rt, 24 h, 12 91%; (ii) DIBAL-H (2.9 equiv.), PhMe, −10 °C to rt, 20 h, 14 quant.; (iii) Ac2O (2.2 equiv.), Et3N (3 equiv.), DMAP (10 mol-%), CH2Cl2, 0 °C to rt, 25 h, 15; (iv) morpholine (1.9 equiv.), Pd(PPh3)4 (5 mol-%), THF, reflux, 5 days, 3 83% (two steps).
Ijms 24 01167 sch004
Ijms 24 01167 sch005 550
Scheme 5. Acyl-Claisen rearrangement and cyclisation. Reagents and conditions: (i) TiCl4.2THF (1 equiv.), i-Pr2NEt (1.5 equiv.), CH2Cl2, rt, 24 h, 1 85%; (ii) OsO4 (2.5 mol-%), NMO (3 equiv.), t-BuOH/H2O (1:1), rt, 4 days, syn-17 12%, 16 88%; (iii) 2M HCl, MeOH, reflux, 4 h, 18 94%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 19 h, 19 56%. 20 quant.
Scheme 5. Acyl-Claisen rearrangement and cyclisation. Reagents and conditions: (i) TiCl4.2THF (1 equiv.), i-Pr2NEt (1.5 equiv.), CH2Cl2, rt, 24 h, 1 85%; (ii) OsO4 (2.5 mol-%), NMO (3 equiv.), t-BuOH/H2O (1:1), rt, 4 days, syn-17 12%, 16 88%; (iii) 2M HCl, MeOH, reflux, 4 h, 18 94%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 19 h, 19 56%. 20 quant.
Ijms 24 01167 sch005
Ijms 24 01167 sch006 550
Scheme 6. Synthesis of esters. Reagents and conditions: (i) Et3N (2 equiv.), DMAP (5 mol-%), RCOCl (1.2 equiv.), CH2Cl2, 0 °C to rt, 4–23 h, 21–23 72–88%; (ii) Pd/C (10% w/w), H2, EtOAc, rt, 22–24 h, 25–27 (64%–quant.); (iii) Et3N (2 equiv.), DMAP (5 mol-%), BzCl (1.2 equiv.), CH2Cl2, 0 °C–rt, 21 h, 24 48%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 19 h, 28 quant.
Scheme 6. Synthesis of esters. Reagents and conditions: (i) Et3N (2 equiv.), DMAP (5 mol-%), RCOCl (1.2 equiv.), CH2Cl2, 0 °C to rt, 4–23 h, 21–23 72–88%; (ii) Pd/C (10% w/w), H2, EtOAc, rt, 22–24 h, 25–27 (64%–quant.); (iii) Et3N (2 equiv.), DMAP (5 mol-%), BzCl (1.2 equiv.), CH2Cl2, 0 °C–rt, 21 h, 24 48%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 19 h, 28 quant.
Ijms 24 01167 sch006
Ijms 24 01167 sch007 550
Scheme 7. Synthesis of nitrogen-containing derivatives. Reagents and conditions: (i) MsCl (1.5 equiv.), Et3N (1.4 equiv.), CH2Cl2, 0 °C to rt, 2.5 h, 31; (ii) NaN3 (3.8 equiv.), DMF, 85–100 °C, 27 h, 29 78% (two steps) and 30 25% (two steps); (iii) phenylacetylene (1.5 equiv.), Cu2SO4.5H2O (0.16 equiv.), sodium L-ascorbate (0.2 equiv.), MeCN, rt, 4 days, 32 74%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 5 days, 33 29%.
Scheme 7. Synthesis of nitrogen-containing derivatives. Reagents and conditions: (i) MsCl (1.5 equiv.), Et3N (1.4 equiv.), CH2Cl2, 0 °C to rt, 2.5 h, 31; (ii) NaN3 (3.8 equiv.), DMF, 85–100 °C, 27 h, 29 78% (two steps) and 30 25% (two steps); (iii) phenylacetylene (1.5 equiv.), Cu2SO4.5H2O (0.16 equiv.), sodium L-ascorbate (0.2 equiv.), MeCN, rt, 4 days, 32 74%; (iv) Pd/C (10% w/w), H2, EtOAc, rt, 5 days, 33 29%.
Ijms 24 01167 sch007
Table
Table 1. Anti-proliferative activities when cells treated with compound (10 µM). Values are given as the average ± standard error of three experimental replicates. Most active compounds, selected for IC50 determination, in highlighted rows.
Table 1. Anti-proliferative activities when cells treated with compound (10 µM). Values are given as the average ± standard error of three experimental replicates. Most active compounds, selected for IC50 determination, in highlighted rows.
CompoundRelative Thymidine Uptake at 10 µM (%)
HCT-116MDA-MB-231
1642.70 ± 1.4754.48 ± 2.17
1867.44 ± 8.1686.62 ±3.64
1990.01 ± 0.97100.40 ± 2.66
2087.83 ± 1.2092.22 ± 2.66
2148.92 ± 1.4860.60 ± 1.68
2244.64 ± 1.0850.69 ± 2.37
2342.31 ± 0.9360.45 ± 0.47
2434.80 ± 0.1544.15 ± 1.78
2586.01 ± 0.65104.00 ± 3.48
2690.38 ± 2.00105.19 ± 5.09
2755.86 ± 0.8675.04 ± 3.06
2923.72 ± 1.5436.53 ± 1.32
3076.48 ± 3.9796.57 ± 2.88
3228.02 ± 2.1744.80 ± 0.37
3316.48 ± 0.2934.09 ± 1.58
Arctigenin *-84.81 ± 5.96 [32]
* = determined using MTT assay, after 24 h [32].
Table
Table 2. IC50 values. Values are given as the average ± standard error of three experimental replicates. Most active compounds in highlighted rows.
Table 2. IC50 values. Values are given as the average ± standard error of three experimental replicates. Most active compounds in highlighted rows.
CompoundMean IC50 ± Standard Error (µM)
HCT-116MDA-MB-231
246.10 ± 1.536.90 ± 0.10
295.17 ± 1.136.23 ± 0.63
323.27 ± 1.136.89 ± 0.20
335.29 ± 1.177.45 ± 0.70
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Paulin, E.K.; Leung, E.; Pilkington, L.I.; Barker, D. Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation. Int. J. Mol. Sci. 2023, 24, 1167. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021167

AMA Style

Paulin EK, Leung E, Pilkington LI, Barker D. Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation. International Journal of Molecular Sciences. 2023; 24(2):1167. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021167

Chicago/Turabian Style

Paulin, Emily K., Euphemia Leung, Lisa I. Pilkington, and David Barker. 2023. "Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation" International Journal of Molecular Sciences 24, no. 2: 1167. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021167

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