Chinese Chemical Letters  2016, Vol. 27 Issue (06): 948-952   PDF    
Synthesis and antiviral activities of novel 1,4-pentadien-3-one derivatives bearing an emodin moiety
Wu Jian1, Zhu Yun-Ying1,2, Zhao Yong-Hui3, Shan Wei-Li3, Hu De-Yu1, Chen Ji-Xiang1, Liu Deng-Yue1, Li Xiang-Yang1, Yang Song1     
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Research and Development Center for Fine Chemicals, Guizhou University, Guiyang 550025, China; ;
b School of Chemical Engineering, Guizhou Institute of Technology, Guiyang 550001, China; ;
c Institute for the Control of Agrochemicals, Ministry of Agriculture, Beijing 100125, China
Abstract: A series of 1,5-diaryl-1,4-pentadien-3-one derivatives bearing an emodin group were designed and synthesized by the combination of natural products. The antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo were evaluated. Some of the derivatives displayed promising curative effect and protective activity against TMV. Compound D5 showed appreciable curative bioactivity on TMV approximately of 50% at 306.2 mg/mL, which was superior to ningnanmycin (409.3 mg/mL).
Key words: 1,4-Pentadien-3-one derivatives     Emodin     Synthesis     Antiviral activity    
1. Introduction

Viruses in crops are infectious particles,posing the risk of host genome integration [1] and leading to serious damage and enormous economic loss in primary agricultural crops,as well as vegetables and tobacco [2]. Taking tobacco mosaic virus (TMV) as an example,it is known as ‘‘plant cancer’’ and causes up to $100 million of economic loss each year worldwide [3]. Controlling viral diseases in plants has been extremely difficult thus far. Hence,the development of new antiviral molecules has attracted more and more attention.

Natural product-based antiviral agents have attracted more attention in recent decades due to their good activity,unique mode of action with low mammalian toxicity,and environmental friendliness [4, 5]. Several natural products such as seco-pregnane steroids [6],triterpenoid glycosides [7, 8],eudesmanolides,[9] triterpene saponins,[10] limonoids [11] etc. were found to show strong antiviral activities. In particular,an alkaloid named antofine from Cynanchum komarovii [12] showed excellent anti-TMV activity,and a large number of antofine-based agrochemicals with excellent anti-TMV activity were synthesized by Wang and co-workers [13-19]. NK-007,an antofine-based alkaloid demonstrates outstanding antiviral activity and was chosen for further development as a potent anti-TMV agent [20].

1,4-Pentadien-3-one is an important curcumin analogue with numerous potential biological activity [21-24] and serves an important function in discovering new antiviral molecules. In previous works,a series of 1,4-pentadien-3-one analogues containing pyrozole [25],quinazoline [1, 26, 27],glucopyranoside [28] and 1,3,4-oxadiazole moieties [29] with excellent antiviral activity against TMV and cucumber mosaic virus (CMV) have been reported. Song and co-workers also disclosed a series of 1,4- pentadien-3-one analogues containing rutin,which showed excellent anti-viral activities against TMV and CMV. This is a successful example for design of antiviral molecules by combination of two sub-structures of natural product analogues [30]. Continuing these investigations,the naturally derived molecule emodin has received increasing attention due to its broad spectrum bioactivity [31-36]. Encouraged by those descriptions above,we sought to synthesize some 1,4-pentadien-3-one derivatives bearing an emodin moiety by a combination of two structures of natural products,which may result in new 1,4- pentadien-3-one derivatives with good anti-viral activity. Accordingly, in this work,an attempt was made to link these two structures via a methylene ether (Scheme 1). Results of bioassays indicate that most synthesized compounds exhibit good antiviral activities against TMV and CMV. In particular,the EC50 value of compound D5 against CMV was 306.2 mg/mL,which was much better than that of Ningnanmycin (409.3 mg/mL). To the best of our knowledge,this is the first report on antiviral activities of 1,4- pentadien-3-one analogs that includes emodin moieties to date.

Download:
Scheme. 1. The molecular design of target compounds.

2. Experimental 2.1. Synthesis

nless noted,all solvents and reagents were freshly distilled or purified according to standard procedures. The 1H NMR and 13C NMR spectra (solvent CDCl3 or MeOD or DMSO-d6) were measured with a JEOL-ECX 500 NMR spectrometer operating at 500 and 125 MHz at room temperature with tetramethylsilane (TMS) as an internal standard,and chemical shifts are expressed in δ(ppm). Mass spectral studies were conducted on an Agilent 5973 organic mass spectrometer. The melting points of the compounds were determined on an XT-4 binocular microscope (Beijing Tech Instrument Co.,China) and were not corrected. Analytical thinlayer chromatography (TLC) was performed on silica gel GF254 (400 mesh).

General procedures for synthesis of intermediate B: A mixture of emodin (2.20 g,8.14μmol) and K2CO3 (10.13 g,73.27μmol) was stirred in acetone (150 mL),and Me2SO4 (6.95 mL, 73.27μmol) was added dropwise. The mixture was heated under reflux for 16 h,concentrated in vacuo,poured into 100 mL of water, and filtered to obtain a light yellow solid A (2.51 g,98.0%). A mixture of A (1.60 g,5.12μmol),NBS (1.06 g,5.94μmol),AIBN (40 mg),and 150 mL CCl4 was refluxed for 18 h. The light yellow solid was washed with water and filtered. The solid was chromatographed on silica gel (200-300 mesh) with petroleum ether: CH2Cl2 gradient (1:1 to 0:1) to obtain a light yellow solid (1.34 g).

General procedures for the preparation of intermediates C1 to C18: 2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde was reacted with acetone in the presence of base (NaOH in water) at room temperature for 18 h. The solution was acidified to obtain (E)-4-(2-hydroxyphenyl)-3-buten-2-one or (E)-4-(4-hydroxyphenyl)- 3-buten-2-one. The key intermediates (1E,4E)-1,5-diaryl-1,4- pentadien-3-ones (C1 to C18) were synthesized by reacting (E)-4- (2-hydroxyphenyl)-3-buten-2-one or (E)-4-(4-hydroxyphenyl)-3- buten-2-one with different aldehydes in the presence of base (NaOH in water) at room temperature for 12 h. The pH value of the mixture was adjusted with diluted hydrochloric acid to 5-6 and then filtered to obtain the solid.

General synthetic procedures for compounds D1 to D18: A mixture of B (281μmol),(1E,4E)-1,5- diaryl-1,4-pentadien-3- one (C1 to C18,281μmol),K2CO3 (843μmol),and 10 mg KI was stirred under reflux for about 2 h and concentrated in vacuo. The residue was poured into 50 mL water and filtered. The solid was chromatographed on silica gel (200-300 mesh) to obtain 1,3,8-trimethoxy-6-((2/4-((1E,4E)-3-oxo-5-aryl-1,4-pentadien- 1-yl)phenoxy)methyl)-9,10-anthraquinone derivatives. The physical characteristics,1H NMR and 13C NMR for all the synthesized compounds are listed in the Supporting information.

2.2. Antiviral bioassay against TMV and CMV

obacco seeds were provided by the Guizhou Institute of Tobacco. Chenopodium amaranticolor seeds were provided by Northwest Agriculture and Forestry University. The curative, protection,and inactivation effects against TMV and the curative effect against CMV in vivo were measured according to a previously described procedure [1, 2]. The commercial compound ningnanmycin was used as a comparison. Three repetitions were conducted for each sample.

3. Results and discussion 3.1. Chemistry

he synthetic protocol of the 1,4-pentadien-3-one derivatives with an emodin moiety is depicted in Scheme 2. First,1,3,8- trimethoxy-6-methyl-9,10-anthraquinone (A) was obtained with a good yield (up to 98%) by reaction of emodin with Me2SO4 in the presence of base (K2CO3) in refluxing acetone. Key intermediate 3- (bromomethyl)-1,6,8-trimethoxy-9,10-anthraquinone (B) was then synthesized by reacting A with NBS in the present of AIBN in CCl4 under reflux condition for 18 h in good yield [37, 38]. AIBN instead of benzoyl peroxide was used to reduce unwanted byproducts [37, 38]. Second,intermediates C1 to C18 were synthesized in good yields via two condensation reaction in presence of base (KOH) by the treatment of acetone with different aromatic aldehyde. Finally,the title compounds D1 to D18 were readily synthesized by treatment of (1E,4E)-1,5-diaryl-1,4-pentadien-3- ones with intermediate B in alkaline condition (K2CO3) in acetone at 50℃,and KI was added as a catalyst to boost reaction times [1].

Download:
Scheme. 2. Synthesis of compounds D1–D18.

The structures of the synthesized compounds (D1 to D18) were established on the basis of the spectroscopic data. As indicated by 1H NMR,the coupling constants of the double bonds’ protons were about 16.0 Hz. The position of the doublets may overlap with that of aryl protons. All aryl protons showed multiplets at δ6.77 to δ7.89. The main characteristic of the 1H NMR spectra for the compounds was the presence of a singlet δH 5.28 for -CH2-O- protons,which connected the 9,10-anthraquinone part with the 1,4-pentadien-3-one moiety. Three O-CH3 absorption peaks showed singlet at 3.93,3.97 and 4.00 ppm,respectively. The typical carbon resonance frequencies at δC 181.49-189.24, 69.53 and 55.89-56.69 ppm in 13C NMR also confirmed the existence of C=O,-CH2-O- and three O-CH3,respectively.

3.2. Antiviral activities against TMV

he inhibitory effects of the 1,4-pentadien-3-one derivatives on TMV were evaluated and listed in Table 1. The results indicated that compounds D1 to D18 displayed weak to good antiviral activities against TMV. Some of them showed promising curative effect and protective activities,with curative and protective rates ranging from 22.8% to 52.6% and 19.2% to 56.8%,respectively. Particularly,compounds D3,D4 and D5 showed 48.3%,50.1%,and 52.6% curative effects at 500 mg/mL,respectively. The protective activity of compounds D5 and D11 (55.4% and 56.8%,respectively) were close to that of commercial ningnanmycin (58.7%). Antiviral activities of target compounds were affected by both variation of different substitutes on the aryl and the position of (1E,4E)-1,5- diaryl-1,4-pentadien-3-one. In the case that the group linked to the aryl was heterocyclic,both curative and protective activities were improved when the (1E,4E)-1,5-diaryl-1,4-pentadien-3-one was in the 2-position compared to the 4-position. When the Ar was phenyl substituted,compounds with electron-donating groups (such as 2-OCH3,4-CH3) were more effective than those with electron-withdrawing groups (such as 4-NO2,4-F).

Table 1
Inhibition effects of 1,4-pentadien-3-one derivatives against TMV in vivo (500mg/mL).

Further bioassays revealed that D4 and D5 showed promising curative effects against TMV. As shown in Table 2,when the concentration of the compounds decreased,the corresponding curative effect displayed a declining trend. However,it is remarkable that the downtrends of D4 and D5 were gentler than ningnanmycin. At the concentration of 62.5 mg/mL,the curative effect of D4 and D5 were still above 40%,while that of ningnanmycin was as low as 32.1%. The EC50 value of D4 was 419.8 mg/mL,which was similar to that of ningnanmycin (EC50 = 409.3 mg/mL),while D5 (EC50 = 306.2 mg/mL) was even superior to ningnanmycin.

Table 2
Curative effects of compounds D4 and D5 against TMV in vivo.

Curative effects against CMV of synthesized 1,4-pentadien-3- one derivatives were also evaluated. The results listed in Table 3 indicated that most of the title compounds showed weakly curative activity against CMV. Compounds D1 and D11 showed 39% and 33% curative activity,respectively. However,these values were still lower than that of commercial ningnanmycin (43.3%).

Table 3
Curative effects of emodin derivatives against CMV in vivo (500mg/mL).

4. Conclusion

In conclusion,a series of novel 1,3,8-trimethoxy-6-((2/4- ((1E,4E)-3-oxo-5-aryl-1,4-pentadien-1-yl)phenoxy)methyl)-9,10- anthraquinone derivatives were designed and synthesized by combining the substructures of two types of natural products. Compounds D3,D4,D5,and D11 exhibited good activities against TMV in vivo. The antiviral tests showed that when Ar was heterocyclic and the (1E,4E)-1,4-pentadien-3-one was at 2- position,the anti-TMV activity of the corresponding compounds could be enhanced. When Ar was substituted with phenyl, compounds with electron-donating groups (such as 2-OCH3,4- CH3) were better than those with electron-withdrawing groups (such as 4-NO2,4-F). The present report is the first study of the synthesis and antiviral activities of 1,3,8-trimethoxy-6-((2/4- ((1E,4E)-3-oxo-5-aryl-1,4-pentadien-1-yl)phenoxy)methyl)-9,10- anthraquinone derivatives. Further studies are currently underway to optimize the structure to obtain better antiviral activity in these new 1,4-pentadien-3-one derivatives with an emodin group based on these findings.

References
[1] H. Luo, J. Liu, L. Jin, et al. Synthesis and antiviral bioactivity of novel (1E., 4E)-1-aryl-5-(2-(quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one derivatives.. Eur. J. Med. Chem. 63 (2013) 662–669.
[2] B.A. Song, H.P. Zhang, H. Wang, et al. , Synthesis and antiviral activity of novel chiral cyanoacrylate derivatives. J. Agric. Food Chem. 53 (2005) 7886–7891.
[3] ] L. Bos. 100 years of virology: from vitalism via molecular biology to genetic engineering. Trends Microbiol. 8 (2000) 82–87.
[4] X.H. Qian, P.W. Lee, S. Cao. China: forward to the green pesticides via a basic research program. J. Agric. Food Chem. 58 (2010) 2613–2623.
[5] J.N. Seiber. Sustainability and Agricultural and Food Chemistry. J. Agric. Food Chem. 59 (2011) 1–2.
[6] X.H. Yan, J. Chen, Y.T. Di, et al. , Anti-tobacco mosaic virus (TMV) quassinoids from Brucea javanica (L.) Merr. J. Agric. Food Chem. 58 (2010) 1572–1577.
[7] Z.K. Zhang, M.A. Ouyang, Z.J. Wu, Q.Y. Lin, L.H. Xie. Structure-activity relationship of triterpenes and triterpenoid glycosides against tobacco mosaic virus. Planta Med. 73 (2007) 1457–1463.
[8] Z.J. Wu, M.A. Ouyang, C.Z. Wang, Z.K. Zhang. Six new triterpenoid saponins from the leaves of Ilex oblonga and their inhibitory activities against TMV replication. Chem. Pharm. Bull. 55 (2007) 422–427.
[9] Y.T. Li, X.J. Hao, S.F. Li, et al. Eudesmanolides from Wedelia trilobata (L.) Hitchc. as potential inducers of plant systemic acquired resistance. J. Agric. Food Chem. 61 (2013) 3884–3890.
[10] Z.J. Wu, M.A. Ouyang, C.Z. Wang, Z.K. Zhang, J.G. Shen. Anti-tobacco mosaic virus (TMV) triterpenoid saponins from the leaves of Ilex oblonga. J. Agric. Food Chem. 55 (2007) 1712–1717.
[11] Y.H. Ge, K.X. Liu, J.X. Zhang, S.Z. Mu, X.J. Hao. The limonoids and their antitobacco mosaic virus (TMV) activities from Munronia unifoliolata Oliv. J. Agric. Food Chem. 60 (2012) 4289–4295.
[12] T.Y. An, R.Q. Huang, Z. Yang, et al. , Alkaloids from Cynanchum komarovii with inhibitory activity against the tobacco mosaic virus. Phytochemistry 58 (2001) 1267–1269.
[13] M. Wu, G. Han, C. Meng, et al. Design, synthesis, and anti-tobacco mosaic virus (TMV) activity of glycoconjugates of phenanthroindolizidines alkaloids. Mol. Div. 18 (2014) 25–37.
[14] Z.W. Wang, L. Wang, S. Ma, et al. Design, synthesis, antiviral activity, and SARs of 14-aminophenanthroindolizidines. J. Agric. Food Chem 60 (2012) 5825–5831.
[15] Z.W. Wang, P. Wei, Y.X. Liu, Q.M. Wang. D and E rings may not be indispensable for antofine: discovery of phenanthrene and alkylamine chain containing antofine derivatives as novel antiviral agents against tobacco mosaic virus (TMV) based on interaction of antofine and TMV RNA. J. Agric. Food Chem. 62 (2014) 10393–10404.
[16] Y.H. Zheng, Y.X. Liu, Q.M. Wang. Collective asymmetric synthesis of (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine with tert-butanesulfinamide as a chiral auxiliary. J. Org. Chem. 79 (2014) 3348–3357.
[17] B. Su, C.L. Cai, M. Deng, et al. Design, synthesis, antiviral activity, and SARs of 13asubstituted phenanthroindolizidine alkaloid derivatives. Bio, Med. Chem. Lett. 24 (2014) 2881–2884.
[18] H.J. Song, Y.X. Liu, Y. Liu, L.Z. Wang, Q.M. Wang. Synthesis and antiviral and fungicidal activity evaluation of b-carboline, dihydro-β-carboline, tetrahydrob-carboline alkaloids, and their serivatives. J. Agric. Food Chem. 62 (2014) 1010–1018.
[19] Z.W. Wang, A.Z. Feng, M.B. Cui, et al. , First discovery and stucture-activity relationship study of phenanthroquinolizidines as novel antiviral agents against tobacco mosaic virus (TMV). PLoS ONE 7 (2012) e52933.
[20] Q.M. Wang, K.L. Wang, M. Wu, et al. , Application of tylophorine-like alkaloid organic acid salt derivative to prepare the pesticide formulations for preventing and controlling plant diseases. Chem. Abstr. 154 (2010) 3276.
[21] Y.H. Ren, H. Jin, K. Tao, T.P. Hou. Apoptotic effects of, 1,5-bis-(5-nitro-2-furanyl)-1,4-pentadien-3-one on drosophila SL2 cells. Mol. Cell. Tox. 11 (2015) 187–192.
[22] Y. Li, X. Zou, K. Cao, et al. Curcumin analog, 1.5-bis (2-trifluoromethylphenyl)-1,4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity. Toxicol. App. Pharm. 272 (2013) 726–735.
[23] K. Yuan, B.A. Song, L.H. Jin, et al. , Synthesis and biological evaluation of novel, 1-aryl,5(phenoxy-substituted)aryl-1,4-pentadien-3-one derivatives. MedChem-Comm 2 (2011) 585–589.
[24] J.A. Quincoces Suarez, D.G. Rando, R.P. Santos, et al. , New antitumoral agents I: in vitro anticancer activity and in vivo acute toxicity of synthetic, 1, 5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives. Biol. Med. Chem. 18 (2010) 6275–6281.
[25] Z.N. Wang, D.Y. Hu, B.A. Song, et al. , Synthesis and biological activity of, 1,5-bis(substituted pyrazol-4-yl)-1,4-pentadien-3-one derivatives. Chin. J. Org. Chem. 29 (2009) 1412–1418.
[26] J. Ma, P. Li, X.Y. Li, et al. , Synthesis and antiviral bioactivity of novel, 3-((2-(1E, 4E)-3-oxo-5-arylpenta-1,4-dien-1-yl)phenoxy)methyl)-4(3H)-quinazolinone derivatives. J. Agric. Food Chem. 62 (2014) 8928–8934.
[27] C.W. Long, P. Li, M.H. Chen, et al. Synthesis, anti-tobacco mosaic virus and cucumber mosaic virus activity, and 3D-QSAR study of novel 1,4-pentadien-3-one derivatives containing 4-thioquinazoline moiety,. Eur. J. Med. Chem. 102 (2015) 639–647.
[28] M.H. Chen, D.Y. Hu, X.Y. Li, et al. , Antiviral activity and interaction mechanisms study of novel glucopyranoside derivatives. Biol. Med. Chem. Lett. 25 (2015) 3840–3844.
[29] X.H. Gan, D.Y. Hu, P. Li, et al. Design, synthesis, antiviral activity and threedimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety. Pest. Manage. Sci. 72 (2016) 534–843.
[30] Y. Han, Y. Ding, D.D. Xie, et al. Design, synthesis, and antiviral activity of novel rutin derivatives containing 1,4-pentadien-3-one moiety. Euro. J. Med. Chem. 92 (2015) 732–737.
[31] F. Cao, W. Peng, X.L. Li, et al. , Emodin is identified as the active component of ether extracts from rhizoma Polygoni Cuspidati, for anti-MRSA activity. Can. J. Physiol. Pharm. 93 (2015) 485–493.
[32] N.R. Thimmegowda, C. Park, B. Shwetha, et al. , Synthesis and antitumor activity of natural compound aloe emodin derivatives. Chem. Biol. Drug Des. 85 (2015) 638–644.
[33] J.W. Han, D.W. Shim, W.Y. Shin, et al. , Anti-inflammatory effect of emodin via attenuation of NLRP3 inflammasome activation. Int. J. Mol. Sci. 16 (2015) 8102–8109.
[34] P.C. Thacker, D. Karunagaran. Curcumin and emodin down-regulate TGF-b signaling pathway in human cervical cancer cells. PLoS ONE 10 (2015) e0120045.
[35] J.C. Ma, H. Li, S. Wang, et al. , The anthraquinone derivative emodin inhibits angiogenesis and metastasis through downregulating Runx2 activity in breast cancer. Int. J. Oncol. 46 (2015) 1619–1628.
[36] S.J. Chang, S.H. Huang, Y.J. Lin, Y.Y. Tsou, C.W. Lin. Antiviral activity of Rheum palmatum methanol extract and chrysophanol against Japanese encephalitis virus. Arch. Pharm. Res. 37 (2014) 1117–1123.
[37] M. Koyama, K. Takahashi, T.C. Chou, et al. Intercalating agents with covalent bond forming capability. A novel type of potential anticancer agents., 2. Derivatives of chrysophanol and emodin. J. Med. Chem. 32 (1989) 1594–1599.
[38] H. Falk, T. Tran. Synthesis and properties of an ω,ω'-appended eighteen carbon chains hypericin derivative. Monatsh. Chem. 127 (1996) 717–723.