Design and Synthesis of Novel Janus Dendrimers as Lipophilized Antioxidants

Abstract

In the search for better antioxidants with more satisfactory lipophilicity, a series of Janus dendrimers that consisted of gallic acid and alkyl chains as the peripheral groups, were designed and synthesized. These dendrimers take advantage of a dendritic display to carry multi-antioxidants and multi-lipophilic moieties simultaneously. Consequently, the resulting dendrimers, which showed satisfactory lipophilicity and better antioxidant activity than the gallic acid monomer, are potential novel lipophilized antioxidant agents.

Key words

Janus dendrimers - gallic acid - antioxidant - lipophilization - polyphenols

• References and Notes

• 1 For a review, see: Khadem S, Marles RJ. Molecules 2010; 15: 7985
• 2 Kang MS, Oh JS, Kang IC, Hong SJ, Choi CH. J. Microbiol. 2008; 46: 744
• 3 Kratz JM, Andrighetti-Frohner CR, Leal PC, Nunes RJ, Yunes RA, Trybala E, Bergstrom T, Barardi CR. M, Simoes CM. O. Biol. Pharm. Bull. 2008; 31: 903
• 4 Gomes CA, da Cruz TG, Andrade JL, Milhazes N, Borges F, Marques MP. M. J. Med. Chem. 2003; 46: 5395
• 5 Lu ZB, Nie GJ, Belton PS, Tang HR, Zhao BL. Neurochem. Int. 2006; 48: 263
• 6 For a review, see: Figueroa-Espinoza MC, Villeneuve P. J. Agric. Food Chem. 2005; 53: 2779
• 7a Buisman GJ. H, van Helteren CT. W, Kramer GF. H, Veldsink JW, Derksen JT. P, Cuperus FP. Biotechnol. Lett. 1998; 20: 131
• 7b Ha TJ, Nihei KI, Kubo I. J. Agric. Food Chem. 2004; 52: 3177
• 7c Yu XW, Li YQ, Wu D. J. Mol. Catal. B: Enzym. 2004; 30: 69
• 7d Medina I, Lois S, Alcantara D, Lucas R, Morales JC. J. Agric. Food Chem. 2009; 57: 9773
• 8a Mammen M, Choi SK, Whitesides GM. Angew. Chem. Int. Ed. 1998; 37: 2755
• 8b Tomalia DA. New J. Chem. 2012; 36: 264
• 9a Halkes SB. A, Vrasidas I, Rooijer GR, van den Berg AJ. J, Liskamp RM. J, Pieters RJ. Bioorg. Med. Chem. Lett. 2002; 12: 1567
• 9b Nakazono M, Ma L, Zaitsu K. Tetrahedron Lett. 2002; 43: 9185
• 10 For a review, see: Caminade AM, Laurent R, Delavaux-Nicot B, Majoral JP. New J. Chem. 2012; 36: 217
• 11 Feng XS, Pinaud J, Chaikof EL, Taton D, Gnanou Y. J. Polym. Sci., Part A: Polym. Chem. 2011; 49: 2839
• 12 Guillot M, Eisler S, Weller K, Merkle HP, Gallani JL, Diederich F. Org. Biomol. Chem. 2006; 4: 766
• 13 Fuchs S, Pla-Quintana A, Mazeres S, Caminade AM, Majoral JP. Org. Lett. 2008; 10: 4751
• 14a Wang Y, Grayson SM. Adv. Drug Delivery Rev. 2012; 64: 852
• 14b Cho BK, Jain A, Nieberle J, Mahajan S, Wiesner U, Gruner SM, Turk S, Rader HJ. Macromolecules 2004; 37: 4227
• 14c Choy LS, Chow HF. Synlett 2013; 24: 201
• 15 Pan JZ, Wen M, Yin DQ, Jiang B, He DS, Guo L. Tetrahedron 2012; 68: 2943
• 16 Pan JZ, Guo L, Ouyang L, Yin DQ, Zhao Y. Synlett 2012; 1937
• 17 Convergent Synthesis of Dendrons; Typical Procedure for 4: l-Lysine methyl ester hydrochloride (0.91 g, 5 mmol), 3 (4.62 g, 10.5 mmol), EDCI (10.5 mmol), and HOBt (10.5 mmol) were dissolved in CH₂Cl₂ (50 mL). The reaction mixture was stirred at room temperature for 24 h, then the solution was washed with 1 M HCl (10 mL), 1 M NaHCO₃ (10 mL), and brine (10 mL), and the organic layer was dried over anhydrous Na₂SO₄. After concentration, the crude product was recrystallized by EtOAc to obtain 4 (78%) as a white solid; mp 160–161 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.46–1.54 (m, 2 H, Lys-γ-CH ₂), 1.61–1.70 (m, 2 H, Lys-β-CH ₂), 1.83–2.00 (m, 2 H, Lys-δ-CH ₂), 3.42–3.46 (m, 2 H, Lys-ω-CH ₂), 3.78 (s, 3 H, OCH ₃), 4.75–4.78 (m, 1 H, Lys-α-H), 5.01–5.07 (m, 12 H, 6 × Ph-CH ₂), 6.27 (br s, 1 H, CONH), 6.83 (br s, 1 H, CONH), 7.10 (s, 2 H, GA-Ph-H), 7.17 (s, 2 H, GA-Ph-H), 7.20–7.37 (m, 30 H, OBn-Ph-H). MS (ESI): m/z [M+Na]⁺ calcd for C₆₃H₆₀N₂NaO₁₀ ⁺: 1027.41; found: 1027.36. Anal. Calcd for C₆₃H₆₀N₂O₁₀: C, 75.28; H, 6.02; N, 2.79; O, 15.92. Found: C, 75.14; H, 5.97; N, 2.69; O, 15.88.
• 18 Data of dendron 6: Yield: 65%; white solid; mp 170–172 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.16–1.77 (m, 18 H, 3 × Lys-γ-CH ₂+3 × Lys-β-CH ₂+3 × Lys-δ-CH ₂), 3.33–3.41 (m, 6 H, 3 × Lys-ω-CH ₂), 3.60 (s, 3 H, OCH ₃), 4.67–4.69 (m, 3 H, 3 × Lys-α-H), 4.89–5.02 (m, 24 H, 12 × Ph-CH ₂), 6.80–7.50 (m, 68 H, Ph-H). ESI-TOF-MS: m/z [M+Na]⁺ calcd for C₁₃₁H₁₂₈N₆NaO₂₀ ⁺: 2127.908; found: 2127.825. Anal. Calcd for C₁₃₁H₁₂₈N₆O₂₀: C, 74.69; H, 6.12; N, 3.99; O, 15.19. Found: C, 74.58; H, 6.07; N, 3.93; O, 15.11.
• 19 Data of dendron 11: Yield: 70%; colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.86–0.90 (t, J = 6.4 Hz, 12 H, 4 × CH ₃), 1.25 (br s, 80 H, 40 × myristic acid CH ₂), 1.58–1.60 (m, 8 H, 4 × myristic acid-β-CH ₂), 2.27–2.34 (m, 8 H, 4 × myristic acid-α-CH ₂), 2.63–2.72 (m, 12 H, 6 × succinic acid CH ₂), 3.60–3.69 (m, 12 H, 6 × NCH ₂), 4.17–4.23 (m, 12 H, 6 × NCH₂CH ₂), 5.12 (s, 2 H, Ph-CH ₂), 7.35–7.36 (m, 5 H, Ph-H). ESI-TOF-MS: m/z [M+Na]⁺ calcd for C₈₇H₁₅₁N₃NaO₁₇ ⁺: 1533.094; found: 1533.074. Anal. Calcd for C₈₇H₁₅₁N₃O₁₇: C, 69.15; H, 10.07; N, 2.78; O, 18.00. Found: C, 69.08; H, 10.02; N, 2.71; O, 17.93.
• 20 Dodo K, Minato T, Noguchi-Yachide T, Suganuma M, Hashimoto Y. Bioorg. Med. Chem. 2008; 16: 7975
• 21 Synthesis of Janus Dendrimers; Typical Procedure for 1: Dendron 5 (0.99 g, 1 mmol), HOBt (1.1 mmol), HBTU (1.1 mmol), DIPEA (2 mmol) were dissolved in CH₂Cl₂ (30 mL) and the reaction mixture was stirred at room temperature for 30 min. The above solution was added dropwise into ethylenediamine (3 g, 50 mmol) in CH₂Cl₂ (30 mL). After stirring at room temperature for 24 h, the solution was washed with 10% citric acid (10 mL), 1 M NaHCO₃ (10 mL), and brine (10 mL), and the organic layer was dried over anhydrous Na₂SO₄. After concentration, 13 (1.01 g, 98%) was obtained for the next step without further purification. Dendron 13 (516 mg, 0.5 mmol), 10 (312 mg, 0.5 mmol), HBTU (0.6 mmol), HOBt (0.6 mmol), and DIPEA (1 mmol) were dissolved in CH₂Cl₂ (30 mL) and the reaction mixture was stirred at room temperature for 24 h. The solution was then concentrated under vacuum and the residue was purified by silica-gel column chromatography to obtain 14 as a white waxy solid. 10% Pd/C (100 mg) was added to a solution of 14 in MeOH–CH₂Cl₂ (3:1 v/v, 30 mL) and the reaction mixture was stirred under a hydrogen atmosphere for 24 h in the dark, filtered through a membrane filter, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 1 (76%, two steps from 13) as a white foam. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.83–0.86 (m, 6 H, 2 × CH ₃), 1.23 (br s, 42 H, 20 × myristic acid CH ₂+Lys-γ-CH ₂), 1.45–1.49 (m, 6 H, 2 × myristic acid-β-CH ₂+Lys-β-CH ₂), 1.70 (br s, 2 H, Lys-δ-CH ₂), 2.23–2.31 (m, 4 H, 2 × myristic acid-α-CH ₂), 2.50–2.57 (m, 4 H, 2 × succinic acid CH ₂), 3.08–3.17 (m, 6 H, Lys-ω-CH ₂+NHCH ₂CH ₂NH), 3.47–3.60 (m, 4 H, 2 × NCH ₂), 4.04–4.17 (m, 4 H, 2 × NCH₂CH ₂), 4.26–4.28 (m, 1 H, Lys-α-H), 6.80 (s, 2 H, Ph-H), 6.88 (s, 2 H, Ph-H), 7.84 (br s, 1 H, CONH), 7.93 (br s, 1 H, CONH), 7.95 (br s, 1 H, CONH), 8.06 (br s, 1 H, CONH), 8.65 (br s, 2 H, 2 × Ph-OH), 8.98 (br s, 2 H, 2 × Ph-OH), 9.03 (br s, 2 H, 2 × Ph-OH). MS (ESI): m/z [M+H]⁺ calcd for C₅₈H₉₄N₅O₁₅ ⁺: 1100.6741; found: 1100.6746. GPC: PDI(Mw/Mn) = 1.01. Data of dendrimer 2: Yield: 65% (two steps from 15). ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.76–0.86 (m, 12 H, 4 × CH ₃), 1.22 (br s, 86 H, 40 × myristic acid CH ₂+3 × Lys-γ-CH ₂), 1.36–1.48 (m, 14 H, 4 × myristic acid-β-CH ₂+3 × Lys-β-CH ₂), 1.69 (br s, 6 H, 3 × Lys-δ-CH ₂), 2.22–2.31 (m, 8 H, 2 × myristic acid-α-CH ₂), 2.47–2.61 (m, 12 H, 6 × succinic acid CH ₂), 3.00–3.13 (m, 10 H, 3 × Lys-ω-CH ₂+NHCH ₂CH ₂NH), 3.48–3.59 (m, 12 H, 6 × NCH ₂), 4.05–4.16 (m, 12 H, 6 × NCH₂CH ₂), 4.28–4.30 (m, 3 × Lys-α-H), 6.80–6.89 (m, 8 H, Ph-H), 7.81–7.95 (br s, 4 H, CONH), 8.07 (br s, 3 H, CONH), 8.17 (br s, 1 H, CONH), 8.66 (br s, 4 H, 4 × Ph-OH), 8.99 (br s, 4 H, 4 × Ph-OH), 9.04 (br s, 4 H, 4 × Ph-OH). ESI-TOF-MS: m/z [M+Na]⁺ calcd forC₁₂₈H₂₀₃N₁₁NaO₃₅ ⁺: 2477.4335; found: 2477.4323. GPC: PDI(Mw/Mn) = 1.02.
• 22 Ghose AK, Crippen GM. J. Comput. Chem. 1986; 7: 565
• 23 Evaluation of the Antioxidant Activity by DPPH Assay: Briefly, 2,2-diphenyl-1-picrylhydrazyl (DPPH) in ethanol (200 μM, 2 mL) was added to the test compound (2 mL) at different concentrations in ethanol. In the reaction mixtures, the final concentration of DPPH was 100 μM, and the concentrations of the test compounds were 0.1–10 μM. Each mixture was then shaken vigorously and held for 30 min at room temperature in the dark. The decrease in absorbance of DPPH at 517 nm was measured. All tests were performed in triplicate. EC₅₀ corresponds to effective concentration of test compounds resulting in 50% decolorization of initial DPPH.
• 24 Spizzirri UG, Iemma F, Puoci F, Cirillo G, Curcio M, Parisi OI, Picci N. Biomacromolecules 2009; 10: 1923
• 25 Cho YS, Kim SK, Ahn CB, Je JY. Carbohydr. Polym. 2011; 83: 1617