Synlett 2015; 26(19): 2663-2672
DOI: 10.1055/s-0035-1560591
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Evaluation of the Biological Profile of Novel Analogues of Nucleosides and of Potential Mimetics of Sugar Phosphates and Nucleotides

Nuno M. Xavier*a, Susana D. Lucasb, Radek Jordac, Stefan Schwarzd, Anne Loesched, René Csukd, M. Conceição Oliveirae
  • aCentro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2º Piso, Campo Grande, 1749-016 Lisboa, Portugal   Email: nmxavier@fc.ul.pt
  • bInstituto de Investigação do Medicamento, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
  • cLaboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University & Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • dBereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle (Saale), Germany
  • eCentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Further Information

Publication History

Received: 20 October 2015

Accepted after revision: 22 October 2015

Publication Date:
09 November 2015 (eFirst)

Abstract

The synthesis of purine/triazole 6'-isonucleosides and of glucuronic acid/glucuronamide-derived N-glycosylsulfonohydrazides through efficient and stereo- or regioselective methodologies is described. Their structures were envisaged to mimic nucleosides, sugar phosphates, or nucleotides, and were expected to provide potential inhibitors of therapeutically relevant enzymes, the active sites of which could potentially bind their structural fragments or functional groups. Such enzymes include cholinesterases, carbonic anhydrase II (CA-II) and cyclin-dependent kinase 2 (CDK-2). A (triazolyl)methyl amide-linked disaccharide nucleoside, based on a new prospective structural framework for analogues of nucleoside diphosphate sugars, was synthesized. The synthetic strategies employed unprotected or partially protected carbohydrate derivatives as precursors, including ribose, glucuronic acid, glucuronolactone, and glycopyranosides and relied on stereoselective N-glycosylation, regioselective Mitsunobu coupling and ‘click chemistry’ approaches. Some 6'-isonucleosides and triazole-containing glycoderivatives displayed moderate selective acetylcholinesterase inhibitory activities. The best inhibitor was an aminomethyltriazole 6'-isonucleoside with a K i value of 11.9 μM. N-Glucuronylsulfonohydrazide showed good inhibition of CA-II (K i = 9.5 μM). Molecular docking of the most active compounds into the effected enzymes showed interactions with key amino acid residues for substrate recognition. In addition, the tested compounds did not show toxicity to normal cells.

Supporting Information

 
  • References and Notes

  • 1 Jordheim LP, Durantel D, Zoulim F, Dumontet C. Nat. Rev. Drug Discovery 2013; 12: 447
  • 2 Galmarini CM, Popowycz F, Joseph B. Curr. Med. Chem. 2008; 15: 1072
    • 3a Galmarini CM, Jordheim L, Dumontet C. Expert Rev. Anticancer Ther. 2003; 3: 717
    • 3b Parker WB. Chem. Rev. 2009; 109: 2880
    • 3c Kim J.-H, Yu J, Alexander V, Choi JH, Song J, Lee HW, Kim HO, Choi J, Lee SK, Jeong LS. J. Med. Chem. 2014; 83: 208
  • 4 Parker WB, Secrist JA. III, Waud WR. Curr. Opin. Investig. Drugs. 2004; 5: 592
    • 5a Tedaldia L, Wagner GK. MedChemComm 2014; 5: 1106
    • 5b Chène P. Nat. Rev. Drug Discovery 2002; 1: 665
    • 5c Rajni, Meena LS. Int. J. Infect. Dis. 2010; 14: e682
    • 5d Houslay MD, Schafer P, Zhang KY. J. Drug Discovery Today 2005; 10: 1503
    • 5e Phosphodiesterases as Drug Targets . Francis SH, Conti M, Houslay MD. Springer-Verlag; Berlin, Heidelberg; 2011
    • 5f Lyko F, Brown R. J. Natl. Cancer Inst. 2005; 97: 1498
    • 6a Zhang J, Yang PL, Gray NS. Nature Rev. 2009; 28
    • 6b Grant SK. Cell. Mol. Life Sci. 2009; 66: 1163
  • 7 Malumbres M, Barbacid M. Nat. Rev. Cancer 2009; 9: 153
    • 8a Shapiro GI. J. Clin. Oncol. 2006; 24: 1770
    • 8b Lapenna S, Giordano A. Nat. Rev. Drug Discovery 2009; 8: 547
    • 8c Canavese M, Santo L, Raje N. Cancer Biol. Ther. 2012; 13: 451
  • 9 Cicenas J, Valius M. J. Cancer Res. Clin. Oncol. 2011; 137: 1409
  • 10 Mariaule G, Belmont P. Molecules 2014; 19: 14366
  • 11 Jorda R, Paruch K, Krystof V. Curr. Pharm. Des. 2012; 18: 2974
  • 12 Nemunaitis JJ, Small KA, Kirschmeier P, Zhang D, Zhu Y, Jou YM, Statkevich P, Yao SL, Bannerji R. J. Transl. Med. 2013; 11: 259
    • 13a Kimura K.-i, Bugg TD. H. Nat. Prod. Rep. 2003; 20: 252
    • 13b Rachakonda S, Cartee L. Curr. Med. Chem. 2004; 11: 775
    • 14a Xavier NM, Schwarz S, Vaz PD, Csuk R, Rauter AP. Eur. J. Org. Chem. 2014; 2770
    • 14b Schwarz S, Csuk R, Rauter AP. Org. Biomol. Chem. 2014; 12: 2446
    • 14c Meier C, Ducho C, Görbig U, Esnouf R, Balzarini JJ. Med. Chem. 2004; 47: 2839
    • 15a Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D. Eur. J. Med. Chem. 2013; 70: 165
    • 15b Anand P, Singh B. Arch. Pharmacal. Res. 2013; 36: 375
  • 16 Scozzafava A, Supuran CT. Subcell. Biochem. 2014; 75: 349
  • 17 Carta F, Supuran CT, Scozzafava A. Future Med. Chem. 2014; 6: 1149
    • 18a Lopez M, Paul B, Hofmann A, Morizzi J, Wu QK, Charman SA, Innocenti A, Vullo D, Supuran CT, Poulsen S.-A. J. Med. Chem. 2009; 52: 6421
    • 18b Rodríguez OM, Maresca A, Témpera CA, Bravo RD, Colinas PA, Supuran CT. Bioorg. Med. Chem. Lett. 2011; 21: 4447
  • 19 Chohan TA, Qian H, Pan Y, Chen J.-Z. Curr. Med. Chem. 2015; 22: 237
    • 20a Nair V, Piotrowska DG, Okello M, Vadakkan J. Nucleosides, Nucleotides Nucleic Acids 2007; 26: 687
    • 20b Tino JA, Clark JM, Field AK, Jacobs GA, Lis KA, Michalik TL, McGeever-Rubin B, Slusarchyk WA, Spergel SH. J. Med. Chem. 1993; 36: 1221
    • 20c Nair V. Antiviral Isonucleosides: Discovery, Chemistry and Chemical Biology. In Recent Advances in Nucleosides: Chemistry and Chemotherapy. Chu CK. Elsevier; Oxford; 2002: 149-166
    • 21a Yu HW, Zhang LR, Zhuo JC, Ma LT, Zhang LH. Bioorg. Med. Chem. 1996; 4: 609
    • 21b Yu H.-W, Zhang H.-Y, Yang Z.-J, Min J.-M, Ma L.-T, Zhang L.-H. Pure Appl. Chem. 1998; 70: 435
  • 22 Silva FP. L, Cirqueira ML, Martins FT, Vasconcellos ML. A. A. J. Mol. Struct. 2013; 1052: 189
  • 23 Jiang C, Li B, Guan Z, Yang Z, Zhang L, Zhang L. Bioorg. Med. Chem. 2007; 15: 3019
  • 25 Synthesis of 2-Acetamide-6-chloro-9-(methyl 2,3,4-O-acetyl-6-deoxy-α-d-glucopyranosid-6-yl)purine (2) through Mitsunobu Reaction: To a solution of methyl 2,3,4-O-acetyl-α-d-glucopyranoside (1; 100 mg, 0.31 mmol) in THF (5 mL) under nitrogen, PPh3 (163 mg, 0.62 mmol), diethyl azodicarboxylate (DEAD; 0.62 mmol, 0.1 mL) and 2-acetamido-6-chloropurine (132 mg, 0.62 mmol) were sequentially added. The mixture was stirred at r.r. under nitrogen for 16 h. The solvent was evaporated and the residue was subjected to column chromatography on silica gel (EtOAc–petroleum ether, 1:1 to 1:9) to afford 2 (128 mg, 80%) as a white solid. [α] d 20 +15 (c = 0.3, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H, NH), 8.13 (s, 1 H, H-8), 5.46 (t, J = 9.4 Hz, 1 H, H-3'), 4.96 (d, J 1',2' = 3.5 Hz, 1 H, H-1'), 4.84–4.72 (m, J 2',3' = 10.2 Hz, 2 H, H-2', H-4'), 4.45–4.29 (m, 2 H, H-6'a, H-6'b), 4.11 (ddd, 1 H, H-5'), 3.17 (s, 3 H, OCH3), 2.51 (s, 3 H, CH3, NHAc), 2.12, 2.06, 1.99 (3 × s, 9 H, CH3, OAc). 13C NMR (100 MHz, CDCl3): δ = 170.2, 170.1, 170.1 (CO, NHAc, CO, Ac), 152.8 (C-4), 152.2, 151.5 (C-2, C-6), 145.5 (C-8), 127.6 (C-5), 96.9 (C-1'), 70.6 (C-2'), 69.7 (C-3'), 69.6 (C-4'), 67.5 (C-5'), 55.8 (OCH3), 43.9 (C-6'), 25.3 (CH3, NHAc), 20.9, 20.8, 20.7 (3 × CH3, OAc). HRMS: m/z [M+Na]+ calcd for C20H24ClN5O9: 536.1155; found: 536.1152
  • 26 Crich D, Cai W, Dai Z. J. Org. Chem. 2000; 65: 1291
  • 27 Mangholz SE, Vasella A. Helv. Chim. Acta 1991; 74: 2100
  • 28 Edgar LJ. G, Dasgupta S, Nitz M. Org. Lett. 2012; 14: 4226
    • 29a Batchelor RJ, Green DF, Johnston BD, Patrick BO, Pinto BM. Carbohydr. Res. 2001; 330: 421
    • 29b Lavecchia MJ, Rodríguez OM, Echeverría GA, Pis Diez R, Colinas PA. Carbohydr. Res. 2012; 361: 182
    • 29c Suthagar K, Polsona MI. J, Fairbanks AJ. Org. Biomol. Chem. 2015; 13: 6573
  • 30 Ronchi S, Prosperi D, Thimon C, Morin C, Panza L. Tetrahedron: Asymmetry 2005; 16: 39
  • 31 Girard C, Önen E, Aufort M, Beauvire S, Samson E, Herscovici J. Org. Lett. 2006; 8: 1689
  • 32 Synthesis of N-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 1-Deoxy-1-(2-tosylhydrazin-1-yl)-β-d-glucopyranuronamide (20) through N-Glycosylation: To a solution of N-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-α,β-d-glucopyranuronamide (19; 250 mg. 0.69 mmol) in DMF (1.5 mL), p-toluenesulfonyl hydrazide (145 mg, 0.78 mmol, 1.1 equiv) and glacial acetic acid (4 μL, 0.07 mmol, 0.1 equiv) was added. The reaction mixture was allowed to stand at 40 °C without stirring for 48 h, then the solvent was evaporated under vacuum. Diethyl ether (20 mL) was added to the residue and the mixture was vigorously stirred for 24 h. The mixture was filtered and the white solid was washed with diethyl ether, dichloromethane, and cold methanol to give pure 20 (165 mg, 45%) as a white solid; mp 154–155.7 °C; [α] d 20 –2 (c = 0.4, MeOH). 1H NMR (400 MHz, CD3OD): δ = 7.86 (s, 1 H, H-9), 7.77 (d, J = 8.1 Hz, 2 H, Ha, Ts), 7.43–7.27 (m, 7 H, Hb, Ts, Ph), 5.56 (s, 2 H, CH2, Bn), 4.50, 4.45 (2 × d, J = 15.7 Hz, AB system, CH2-7), 3.85 (d, J 1,2 = 7.9 Hz, 1 H, H-1), 3.65 (d, J 4,5 = 8.5 Hz, 1 H, H-5), 3.49–3.36 (m, 2 H, H-2, H-3, H-4), 2.43 (s, 3 H, Me, Ts). 13C NMR (100 MHz, CD3OD): δ = 172.3 (CO), 145.2 (Cq, Ts), 137.3 (2 × Cq, Ts, Ph), 130.7, 130.0, 129.6, 129.2, 129.0 (CH, Ts, Ph), 91.8 (C-1), 77.6 (C-3), 76.9 (C-5), 73.5, 71.0 (C-2, C-4), 55.0 (CH2, Bn), 35.2 (C-7), 21.5 (CH3, Ts). HRMS: m/z [M+H]+ calcd for C23H28N6O7S: 533.1813; found: 533.1827
  • 34 Synthesis of N-[1-(Methyl 2,3,4-O-acetyl-6-deoxy-α-d-glucopyranosid-6-yl)-1H-1,2,3-triazol-4-yl]methyl-1,2-O-isopropylidene-α-d-glucofuranuronamide (34) through CuI/Amberlyst A21-Catalyzed Cycloaddition: To a solution of N-propargyl 1,2-O-isopropylidene-α-d-glucofuranuronamide (17; 180 mg, mg, 0.66 mmol) in dichloromethane (7 mL), methyl 2,3,4-O-acetyl-6-azido-6-deoxy-α-d-glucopyranoside (23; 0.66 mmol, 229 mg) and CuI/Amberlyste A21 (126 mg) were added. The suspension was stirred overnight at r.t., then the catalyst was filtered off and the solvent was evaporated. The residue was subjected to column chromatography on silica gel (ethyl acetate to ethyl acetate–methanol, 9.5:0.5) to give triazole-linked disaccharide 24 (304 mg, 74%) as a white solid. Data for 24: mp 211–213 °C; [α]D 20 = +25 (c = 0.3, CH3OH). 1H NMR (400 MHz, MeOD): δ = 7.92 (s, 1 H, H-9), 5.93 (d, J 1,2 = 3.4 Hz, 1 H, H-1), 5.40 (t, J 2',3' = J 3',4' = 9.7 Hz, 1 H, H-3'), 5.01–4.80 (m, J 1',2' = 3.7 Hz, J 2',3' = 9.7 Hz, 3 H, H-1', H-2', H-4'), 4.62 (dd, part A of ABX system, J 5',6'a = 2.0 Hz, J 6'a,6'b = 14.2 Hz, 1 H, H-6'a), 4.57–4.46 (m, 4 H, H-2, H-6'b, H-7a, H-7b), 4.38 (d, J 4,5 = 6.3 Hz, 1 H, H-5), 4.25 (dd, J 3,4 = 2.1 Hz, 1 H, H-4), 4.22–4.12 (m, 1 H, H-3, H-5'), 3.14 (s, 3 H, Me), 2.07, 2.02, 1.98 (3 × s, 3 × 3 H, 3 × CH 3, Ac), 1.46 (s, 3 H, CH 3, i-Pr), 1.32 (s, 3 H, CH 3, i-Pr). 13C NMR (100 MHz, MeOD): δ = 171.7, 171.5, 171.4 (3 × CO, Ac), 146.9 (C-8), 125.4 (C-9), 113.0 (Cq, i-Pr), 106.4 (C-1), 97.9 (C-1'), 86.5 (C-2), 82.4 (C-4), 75.8 (C-3), 71.9 (C-3'), 71.4, 71.3 (C-2', C-4'), 71.0 (C-5), 69.0 (C-5'), 55.9 (CH3, OMe), 51.7 (C-6'), 35.7 (C-7), 27.1, 26.4 (2 × CH3, i-Pr), 20.6, 20.6, 20.4 (3 × CH3, Ac). HRMS: m/z [M+H]+ calcd for C25H36N4O14: 617.2301; found: 617.2304.

    • For reviews on ‘click’-coupling strategies and decoupling, see:
    • 35a Bielski R, Witczak ZJ. Chem. Rev. 2013; 113: 2205
    • 35b Bielski R, Witczak ZJ. Paradigm and Advantage of Carbohydrate Click Chemistry Strategy for Future Decoupling. In Click Chemistry in Glycoscience: New Developments and Strategies. Witczak ZJ, Bielski R. John Wiley & Sons, Inc; Hoboken, NJ; 2013: 3-30
  • 36 Wilkinson BL, Long H, Sim E, Fairbanks AJ. Bioorg. Med. Chem. Lett. 2008; 18: 6265
    • 37a Roychoudhury R, Pohl NL. B. Curr. Opin. Chem. Biol. 2010; 14: 168
    • 37b Tedaldia L, Wagner GK. MedChemComm 2014; 5: 1106
  • 38 GOLD, version 5.2; Cambridge Crystallographic Data Centre: Cambridge U. K., www.ccdc.cam.ac.uk/products/gold_suite.
  • 39 Nachon F, Carletti E, Ronco C, Trovaslet M, Nicolet Y, Jean L, Renard P. Biochem. J. 2013; 453: 393
  • 40 MOE, Molecular Operating Environment; Chemical Computing Group: Montreal, Canada, 2013; www.chemcomp.com.
  • 41 Tõugu V. Curr. Med. Chem. 2001; 1: 155
  • 42 Supuran CT. Nat. Rev. Drug Discovery 2008; 7: 168
  • 43 Cozier GE, Leese MP, Lloyd MD, Baker MD, Thiyagarajan N, Acharya KR, Potter BV. L. Biochemistry 2010; 49: 3464