Synthesis of Fucoidan-Mimetic Glycopolymers with Well-Defined

Letter Cite This: ACS Macro Lett. 2018, 7, 330−335

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Synthesis of Fucoidan-Mimetic Glycopolymers with Well-Defined Sulfation Patterns via Emulsion Ring-Opening Metathesis Polymerization Fei Fan,†,§ Chao Cai,*,†,‡,§ Wei Wang,†,‡,§ Lei Gao,†,§ Jun Li,†,§ Jia Li,†,§ Feifei Gu,†,§ Tiantian Sun,†,§ Jianghua Li,†,§ Chunxia Li,†,‡,§ and Guangli Yu*,†,‡,§ †

Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China ‡ Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China § Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China S Supporting Information *

ABSTRACT: The approach developed here offers distinct and well-defined glycopolymers for deciphering the biological roles of natural bioactive polysaccharides. Fucose monomers were chemically synthesized and decorated with specific sulfation patterns including unsulfate, monosulfate, disulfate, and trisulfate groups. The six fucoidan-mimetic glycopolymers (18−23) were successfully fabricated through microwaveassisted ring-opening metathesis polymerization (ROMP) in an emulsion system. The molecular weight (Mw), polydispersity index (PDI), and multiple functional groups were fully characterized by SEC-MALLS-RI and NMR spectroscopy. Three glycopolymers (19, 21, 23) associated with 2-O-sulfation exhibited better inhibitory effects on the H1N1 virus, while glycopolymers (19, 20) with monosulfate groups were more effective against the H3N2 virus. These findings would promote the development of novel anti-influenza A virus (IAV) drugs based on natural fucoidans.

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saccharides with well-defined structures for elucidating the structure−activity relationship of highly sulfated fucoidan. Many efforts have been devoted to the chemical synthesis of fucoidan oligosaccharides.13 Toshima et al. systematically synthesized sulfated tetrafucosides with different sulfation patterns which proved to be highly correlated to their antitumor activities against human breast cancer MCF-7 cells.14 Meanwhile, glycopolymers with pendant saccharides in their linear structure possess an intrinsic “cluster effect” that mimics natural bioactive polysaccharides.15 Tengdelius et al. reported that free radical polymerization could produce the fucoidan mimetic glycopolymers via protection−deprotection chemistry and postsulfation strategy (Figure 1A). The sulfated fucoidan glycopolymer synthesized by cyanoxyl-mediated free-radical polymerization (CMRP) showed similar properties to natural fucoidan in inhibiting HSV-1 binding and entry to cells.16 The glycopolymer fabricated by thiol-mediated chain transfer freeradical polymerization was coated on gold nanoparticles, which

arine species are huge resources that provide abundant bioactive compounds for potential medicinal applications. Fucoidan is an acidic polysaccharide extracted from brown algae1 such as Sargassum thumbergii, Fucus vesiculosus, Ascophyllum nodosum, etc. It mainly consists of an α-1,3- or alternating α-1,3/1,4-linked L-fucose backbone (Figure 1).2 The sulfated fucoidan exhibits a wide range of bioactive properties including anticoagulant,3 antithrombotic,4 antiviral,5 antitumor,6 anti-inflammatory,7 and hypoglycemic effects.8 Recently, the promising opportunities for developing novel antiviral drugs based on algae-derived polysaccharides9 and sialyl oligosaccharide-based glycodendrimers10 have received considerable attention. Our group reported that the fucoidan derived from Kjellmaniella crassifolia blocks influenza A virus (IAV) infection by targeting viral neuraminidase and the cellular EGFR pathway.11 Although algae-derived polysaccharides possess a broad spectrum of antiviral activities, the structure−activity relationship of fucoidan remains unclear. The binding selectivities of fucoidan polysaccharides mainly depend on their primary structures directly associated with their sulfation patterns, fucosidic linkages, as well as molecular weights.12 Thus, it is critical to obtain oligo- and poly© XXXX American Chemical Society

Received: January 19, 2018 Accepted: February 15, 2018

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DOI: 10.1021/acsmacrolett.8b00056 ACS Macro Lett. 2018, 7, 330−335

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ACS Macro Letters

powerful tools to explain the biological functions of natural bioactive polysaccharides. Natural fucoidan possesses abundant fucose with typical αglycosidic linkages, and a facile and efficient synthesis route was employed to achieve an α-fucosidic bond (1) in good yield according to our previous work.20 Scheme 1 first shows how to Scheme 1. Diversified Synthesis of Regioselectively Protected α-Fucose with Terminal Azide Functionalitya

a

Figure 1. Compositional structures and architectures of natural fucoidan polysaccharides and fucoidan-mimetic glycopolymers with random (A)16 or well-defined (B) sulfation patterns.

Reagents and conditions: (a) CSA, CH3CN, PhC(OEt)3, reflux; (b) 1 M HCl; (c) Ac2O, Py; (d) NaH, BnBr, DMF; (e) NaBrO3, Na2S2O4, EtOAc/H2O; (f) Me2C(OMe)2, TsOH·H2O, acetone; (g) 70% AcOH, 80 °C.

displayed selective cytotoxicity to human colon cancer cell lines (HCT116) and nontoxicity to mouse fibroblast cells (NIH3T3).17 Generally, the glycopolymers with pendant fucose could be used to mimic natural fucoidan polysaccharides. However, the relationship between their structural properties and corresponding biological functions is unclear. The glycopolymers synthesized via free radical polymerization through a time-consuming process gave wide polydispersities (PDIs) from 1.32 to 2.15. 18 Furthermore, manipulation of protecting groups after polymerization might damage the functional sites. More importantly, the sulfated positions on the saccharide ring remain unclear through postsulfation strategy.19 Therefore, the synthesis of fucoidanmimetic glycopolymers with well-defined structures remains a big challenge. In our recent work, we explored the protectiongroup-free ring-opening metathesis polymerization (ROMP) in a system of phase-transfer catalysis (PTC).20 A relatively simple step was conducted during the process of polymerization, and multiblock glycopolymers were efficiently prepared over 15 min with a narrow PDI via an emulsion system. Thus, it is reasonable to achieve sulfated glycopolymers via protectiongroup-free ROMP in terms of their functional group tolerance. In this work, the robust polymerization protocol20 was further optimized to obtain fucoidan-mimetic glycopolymers with distinct sulfate groups at specific sites (Figure 1B). All six glycopolymers were tested for their in vitro inhibitory effects against the influenza A (H1N1, H3N2) virus. The fucoidanmimetic glycopolymer with selective 2-O-sulfation showed a relatively higher inhibitory activity against the influenza A (H1N1, H3N2) virus. The sulfation patterns on the fucoidanmimetic glycopolymers were highly relevant to their antiinfluenza virus activities. These novel glycopolymers fabricated by microwave-assisted emulsion polymerization could be

obtain key intermediates 2 (1-azidoethyl 2-O-acetyl-4-Obenzoyl-α-L-fucopyranoside) and 3 through the cyclic 3,4-Oorthobenzoation,21 acetylation, and regioselective ring-opening reaction from α-fucose monomer 1. The structures of these intermediates were confirmed by NMR and MS spectroscopy. We also found that removal of the benzyl group was incompatible with catalytic hydrogenation due to the presence of an azido group at the terminal chain. 1-Azidoethyl 3-Oacetyl-4-O-benzoyl-α-L-fucopyranoside (4) was smoothly obtained under mild oxidative conditions (NaBrO3/Na2S2O4).22 Meanwhile, the 1-azidoethyl 4-O-benzoyl-α-L-fucopyranoside (5) was synthesized in a one-pot synthesis with cyclic 3,4-Oorthobenzoation of intermediate 1 followed by acidic hydrolysis. To obtain the 3,4-di-O-hydoxyl fucose intermediate, 1 was transformed into the cyclic 3,4-O-isopropylidenate in the presence of p-toluenesulfonic acid to afford compound 6 after acetylation, which was later confirmed via NMR analysis. Treatment with 70% acetic acid of compound 6 achieved 1azidoethyl 2-O-acetyl-α-L-fucopyranoside (7) in a quantitative yield. We next studied the condensation of alkynylated exonorbornene (8)20 with unsulfated (1) and sulfated fucosides via a copper-catalyzed azide−alkyne cycloaddition (CuAAC) (Schemes 2 and S1). Glycomonomer 9 (Scheme S1) with no sulfate pendant was easily prepared via the CuAAC reaction in a quantitative yield. The diacylated azidated α-fucoses 2 and 4 were reacted with compound 8 via CuAAC reaction (Scheme S1), and subsequent O-sulfation was performed by standard procedures.23 The glycomonomers 11 and 13 (Scheme S1) were not obtained due to the instability of the cyclic imide unit on the norbornene during the deacetylation procedure (MeOH/MeONa, pH 9−10),24 hence an alternative condition (saturated AcONa/MeOH at 50 °C) was employed to afford the monosulfated fucoside monomers successfully. The monoacylated azidated α-fucoses 5 and 7 were smothly 331


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ACS Macro Letters

the full O-sulfation efficiency, the glycopolymer 18 was manipulated under microwave irradiation at 70 °C for 1 h.25 The chemical shift of the norbornene olefinic signals (6.36 ppm) shifted upfield to polymer olefin signals (5.3−5.9 ppm), indicating complete polymerization of glycomonomers (Figure 2). The SEC-MALLS-RI analysis exhibited a single peak with

Scheme 2. Synthesis of Fucoidan-Mimetic Glycopolymers with Well-Defined Sulfation Patterns via CuAAC and ROMPa

Reagents and conditions: (a) CuSO4·5H2O, Na-ascorbate, THF/ H2O; (b) DTAB, H-G second, MW 75 °C, bis-Tris buffer/DCE = 2/ 1; (c) SO3·Et3N, DMF, MW 70 °C; (d) SO3·Py, DMF, 50 °C; (e) AcONa/MeOH, 50 °C; (f) 1 M NaOH, DMF/H2O = 1/1. a

Figure 2. 1H NMR spectroscopy of the fucoidan-mimetic glycopolymers (18, 19, 20, 21, 22, and 23) in D2O.

transformed onto the polymerizable norbornene via CuAAC reaction followed by sulfation to afford glycomonomers 15 and 17 (Scheme S1). Because the deacylation of disulfated glycomonomers failed under optimized conditions, the global deprotection was manipulated after polymerization. The NMR data of fucoside monomers (9, 11, 13, 15, and 17) are summarized in Table S1 and Table S2 according to the corresponding 1H NMR, 13C NMR, COSY, and HSQC spectra. The optimized emulsion system was confirmed to be compatible with aqueous-soluble monomers in our prior work,20 which could be potentially applied for sulfated saccharides. Fucoside monomers were rapidly polymerized via ROMP initiated by Hoveyda−Grubbs second (H−G second) generation catalyst under microwave irradiation (Schemes 2 and S2), and the final products were afforded after dialysis and lyophilization. The fucoside monomers 9, 11, and 13 were completely converted to their corresponding glycopolymers 18, 19, and 20 with well-defined sulfation patterns. Due to the obstacles in deacylation, the disulfated fucoside monomers 15 and 17 were directly polymerized to obtain protected glycopolymers with desired molecular structures (Scheme 2). These protected glycopolymers were found to be hydrophobic which facilitated dissolution in N,N-dimethylformamide (DMF) instead of an emulsion system. Subsequently, global deprotection in the cosolvent system (DMF/H2O, 1/1) was handled under weak basic circumstance (adjusted with 1 M NaOH) to afford the final glycopolymers 21 and 22 (Scheme 2). The trisulfated fucoside monomer could be smoothly obtained from unsulfated monomer 9, but it could not be effectively polymerized under the general emulsion ROMP procedure. Thus, an alternative postmodification strategy was employed to obtain the trisulfated fucoidan-mimetic 23. The sulfur trioxide triethylamine complex in DMF has been widely used to synthesize highly sulfated polysaccharides. To promote

narrow polydispersity (PDI < 1.20), corresponding to average molecular weights of 82.6, 81.9, 81.4, 65.4, and 64.8 kDa for glycopolymers 18, 19, 20, 21, and 22, respectively (Table 1). The longer retention time for glycopolymer 23 (Mw 127.3 kDa) compared with glycopolymer 18 (Mw 82.6 kDa) was observed, which was consistent with the increased molecular weight of glycopolymer after full O-sulfation. All six fucoidan-mimetic glycopolymers were assayed for their ability to inhibit IAV multiplication in vitro using CPE inhibition assay.26 MDCK cells were initially infected with influenza virus (A/Virginia/ATCC1/2009 (H1N1); H1N1 or A/Aichi/2/68 (H3N2); H3N2) (MOI = 0.1) and then treated with those compounds at 50 μg/mL after removal of the virus inoculum. At 48 h post infection (p.i.), the cell viability was measured by CPE inhibition assay. Table 2 shows that compound 19 significantly promoted the cell viability in H1N1- and H3N2-infected MDCK cells, and CPE increased growth by 35.3% and 31.8%, respectively. This is comparable to the effects of Ribavirin (40.2% and 34.1%). Meanwhile, three glycopolymers (19, 21, and 23) associated with the 2-Osulfation group showed relatively higher inhibitory activities (35.3%, 28.7%, and 26.2%) against the H1N1 virus. Compound 20 also significantly promoted the cell viability in H3N2-infected cells but without obvious inhibition on the H1N1 virus in MDCK cells (Table 2). Considering that the sulfation at 2-OH of fucoidan glycopolymers had good inhibitory activities against both H1N1 and H3N2 viruses and 3-O-sulfation glycopolymers only possessed good inhibition on the H3N2 virus, we supposed that the antiviral activities of fucoidan-mimetic glycopolymers depended more on their sulfation patterns than sulfation degree; further increases in the degree of sulfation (compounds 21−23) could not improve their antiviral activities. Thus, the optimal 332


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ACS Macro Letters Table 1. Characterization of Fucoidan-Mimetic Glycopolymers entry glycopolymer 1 2 3 4 5 6

18 19 20 21 22 23

sulfation patterna

[MM]/[C]b

0S 2S 3S 2,3 S 3,4 S 2,3,4 S

20 20 20 20 20 -

catalyst H−G H−G H−G H−G H−G -

buffer/DCEc

second second second second second

2:1 2:1 2:1 2:1 2:1 -

Td (°C) 75, 75, 75, 75, 75, -

MW MW MW MW MW

te 5 5 5 5 5 -

min min min min min

Mnf (kDa)

Mwf (kDa)

PDIf (Mw/Mn)

yield (%)

77.6 72.1 74.5 58.7 54.4 109.7

82.6 81.9 81.4 65.4 64.8 127.3

1.06 1.14 1.09 1.11 1.19 1.16

>99 >99 >99 >99 >99 >99

a The numbers represent the sulfated position on the sugar ring. Especially the number “0” represents nonsulfation, and “S” is the abbreviation of “sulfation”. bMolar ratio of [monomer (M)]/[catalyst (C)]. cBuffer = bis-Tris buffer (pH 6.0), DCE = dichloroethane ((CH2Cl)2). dProgrammed temperature for microwave-assisted polymerization. MW: microwave heating. eReaction time of complete consumption of the monomer monitored by TLC. fNumber-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (PDI) were determined by SECMALLS-RI. The specific refractive index increment (dn/dc) was determined to be 0.1657 mL/g.20

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Table 2. Virus Infection Inhibition of Fucoidan Mimetics and Ribavirin Against H1N1 and H3N2

Corresponding Authors

*E-mail: [email protected] (C.C.). *E-mail: [email protected] (G.Y.).

virus infection inhibition compound

a

18 (0 S) 19 (2 S) 20 (3 S) 21 (2,3 S) 22 (3,4 S) 23 (2,3,4 S) ribavirin

concentration (μg/mL)

anti-H1N1 (%)

anti-H3N2 (%)

50 50 50 50 50 50 25

2.7 35.3 13.4 28.7 11.5 26.2 40.2

NDb 31.8 41.0 8.0 ND 1.0 34.1

ORCID

Chao Cai: 0000-0003-4377-3989 Author Contributions

The manuscript was written through contributions of all authors. Notes

The authors declare no competing financial interest.

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a

The numbers represent the sulfated position on sugar ring. Especially, the number “0” represents nonsulfation, and “S” is the abbreviation of “sulfation”. bNot detected.

ACKNOWLEDGMENTS This work was financially supported by National Natural Science Foundation of China and NSFC-Shandong Joint Fund for Marine Science Research Centers (21602212, 31670811, 31500646, 81741146, U1606403), Major Science and Technology Projects in Shandong Province (2015ZDJS04002), China Postdoctoral Science Foundation (2016M590664, 2017T100519), Fundamental Research Funds for the Central Universities (201762002), Natural Science Foundation of Shandong Province (ZR2016BB02), Primary Research and Development Plan of Shandong Province (2017GSF221002), Basic Research Funds for Application of Qingdao (17-1-1-63jch), Shandong Provincial Key Laboratory of Glycoscience Industry Alliance, and Taishan Scholar Project Special Funds.

sulfation degree and specific sulfation site are important for the anti-IAV effects of fucoidan-mimetic glycopolymers in vitro. In summary, microwave-assisted ring-opening metathesis polymerization (ROMP) in an emulsion system was employed to fabricate the versatile fucoidan-mimetic glycopolymers with well-defined sulfation patterns. The sulfate group is a critical factor that influences polymerization. We found that the emulsion system was more compatible with sulfated monomers, while the homogeneous solvents were more suitable for protected monomers. Six glycopolymers were successfully obtained including nonsulfated (18), monosulfated (19, 20), disulfated (21, 22), and trisulfated (23) fucoidan mimetics. Their inhibitory effects against the influenza A (H1N1, H3N2) virus were tested in vitro. Based on our results, the virus inhibitory activity of fucoidan mimetics depends more on their sulfation patterns than sulfation degree. We supposed that the single sulfation especially at 2-OH position on fucoidanmimetic glycopolymers could significantly improve the anti-IAV activity. Therefore, the protocol established here is a reasonable basis for the development of antiviral drugs based on the synthetic fucoidan mimetics and natural fucoidan polysaccharides from marine sources.

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AUTHOR INFORMATION

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00056. Experimental details and characterization data (NMR, SEC), cytopathic effect (CPE) inhibition method, and additional references (PDF) 333


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ACS Macro Letters

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Letter

ACS Macro Letters 2015, 70, 2797−2809. (b) Wang, W.; Zhang, P.; Hao, C.; Zhang, X. E.; Cui, Z. Q.; Guan, H. S. In vitro inhibitory effect of carrageenan oligosaccharide on influenza A H1N1 virus. Antiviral Res. 2011, 92, 237−246.

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