ISSN: 0970-020 X ORIENTAL JOURNAL OF CHEMISTRY CODEN: OJCHEG An International Open Free Access, Peer Reviewed Research Journal 2014, Vol. 30, No. (4): Pg. 1639-1645 www.orientjchem.org Synthesis of New Organoselenium Compounds Containing Nucleosides as Antioxidant LAILA M. BREAK1, MAHMOUD A. MOHAMED1,2 and SHAMS H. ABDEL-HAFEZ 1 1,3 1Department of Chemistry, Faculty of Science, Taif University, Taif, Saudi Arabia. 2Department of Biochemistry, Faculty of Agriculture, Cairo University, Cairo, Egypt. 3Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt. *Corresponding author E-mail: [email protected] http://dx.doi.org/10.13005/ojc/300423 (Received: July 30, 2014; Accepted: September 26, 2014) ABSTRACT Selenium containing nucleosides derived from some heterocyclic moieties such as Pyridineselenol, and pyridazineselenol is described herein. Ribosylation of selenol compounds were prepared in good yield by silyation of selenol derivatives with 1-O-acetyl-2,3,5-tri-O-benzoyl- -D-ribofuranose followed by debenzoylation to afford the corresponding free N-nucleosides and -1-(2,3,5-trihydroxy--D-ribofuranosyl)-2-seleno-4,6-dimethylpyridine-3-carbonitrile (6a,7a); b and a-1-(2,3,5-trihydroxy--D-ribofuranosyl)-3-seleno-5,6-diphenylpyridazine-4-carbonitrile (6b,7b). Newly synthesized compounds were characterized using the well known spectroscopic tools (IR, 1HNMR, 13CNMR and mass spectroscopy). Antioxidant activity of six selenonucleoside compounds (1a; 6a; 7a; 1b; 6b and 7b) was evaluated by animal assay model using experimental mice. The resulted data revealed that compounds 6a and 7b showed to be more active as antioxidant with a better performance of scavenging ability than the other compounds. Key words: 1-O-Acetyl-2,3,5-trihydroxy--D-ribofuranose; Nucleosides; Selenium ; Pyridineselenol; pyridazineselenol; antioxidants INTRODUCTION tosylate group by organoselenium nucleophiles. On the other hand in previous work in our laboratory2 From the literature survey indicates that describes the synthesis of selenium-containing few publications have mentioned the incorporation nucleoside analogues, derived from some of selenium atom into nucleosides1,2. In this paper1 heterocyclic moieties such as pyridineselenol, describe the synthesis of selenium- and tellurium- pyridazineselenol and quinolineselenol derivatives containing nucleosides, derived from uridine which which indicated that one of pyridine-moiety 2-(1,3- was prepared in a concise and short synthetic route dihydroxypropylselenyl)-4,6-dimethylpyridine-3- in good yields, by nucleophilic substitution of a carbonitrile which bearing two hydroxyl groups, and 1640 BREAK et al., Orient. J. Chem., Vol. 30(4), 1639-1645 (2014) three of pyridazine-moieties 3-(3-hydroxypropyl catalyst as according to the method of Vorbruggen selenyl)-5,6-diphenylpyridazine-4-carbonitrile, 3- et al.,5 to give the corresponding mixture of - (1,3-dihydroxy propyl selenyl)-5,6- anomeric protected N-nucleoside derivatives and diphenylpyridazine-4-carbonitrile and 3-(oxiran-2- a-anomeric protected N-nucleoside. Separation of ylmethyl selenyl)-5,6-diphenyl- pyridazine-4- the mixture of and a anomers (4a, 5a) and (4b, carbonitrile respectively have definite antioxidant 5b) was carried out by column chromatography in effect. yields ranging from 25-75 % of the corresponding benzoylated nucleosides (4a, 5a, 4b, and 5b) Stimulated by our recent work on the respectively (Scheme 1). synthesis of selenium containing nucleoside analogues2, sulfa drugs3, and the synthesis of Debenzoylation of compounds (4a, 5a, 4b selenium containing amino acid analogues4, we and 5b) were performed by using methanolic decided to expand our interest to the introduction of sodium methoxide solution following Zemplen et an organoselenium compounds in the nucleoside al. method6 to afford the free nucleosides (6 a, 7a, framework and screened their biological activity as 6b and 7b) respectively. antioxidants. The chemical structures of the nucleoside RESULTS AND DISCUSSION derivatives 4a, 4b, 5a, 5b, 6a, 6b, 7a and 7b were established and confirmed on the basis of their Chemistry elemental analyses and spectral data (IR, 1H and Ribosylation of 1a, b were achieved by 13C NMR) (see the Experimental section). refluxing in hexamethyldisilazane (HMDS) to give the silylated derivatives 2a, b. The latter was stirred The IR spectra of compounds (4a, 5a, 4b with 1-O-acetyl-2,3,5-O-benzoyl--D-ribofuranose and 5b) were observed at 2210 cm-1 due to CN (3) in the presence of dry 1,2-dichloroethane as a group and stretching vibration frequencies of the solvent using trimethylsilyl trifluoromethane benzoyl carbonyl groups C=O appeared at 1740, -1 sulfonate (TMS Triflate) (CF3SO2OSiMe3) as a 1730, 1727 and 1724 cm of compounds 4a, 5a, Table 1: Effects of synthesized compounds (1a; 6a; 7a; 1b; 6b and 7b) on SOD; GST activities and GSH-Rd levels Design of treatment SOD GST GSH-Rd (Units/mg protein) (µmol /mgprotein) (mg/g protein) Untreated group,Group 1 35.13 ± 1.25a,b 5.13 ± 0.11a,b 4.21 ± 0.21a,b Compound 1a (100 mg/kg) (Group 2) 35.87 ± 0.51 5.84 ± 0.11 4.10 ± 0.10 Compound 1a (200 mg/kg) (Group 3) 32.21 ± 1.93 6.13 ± 0.25 5.01 ± 0.32 Compound 1b (100 mg/kg) (Group 4) 34.39 ± 1.13 5.10 ± 0.61 4.91 ± 0.27 Compound1b (200 mg/kg) (Group 5) 33.90 ± 1.21 5.82 ± 0.18 5.11 ± 0.22 Compound 6a (100 mg/kg) (Group 6) 39.01 ± 1.15a,b, 3.91 ± 0.26a,b 5.85 ± 0.13a,b Compound 6a (200 mg/kg) (Group 7) 38.90 ± 1. 01 a,b, 6.19 ± 0.10a,b 5.39 ± 0.11a,b Compound 6b (100 mg/kg) (Group 8) 32.49 ± 2.10 5.01 ± 0.72b 4.01 ± 0.12 Compound 6b (200 mg/kg) (Group 9) 33.54 ± 1.42 4.45 ± 0.11 3.92 ± 0.15 Compound 7a (100 mg/kg) (Group 10) 34.54 ± 2.10 5.12 ± 0.32 4.78 ± 0.17 Compound 7a (200 mg/kg) (Group 11) 31.97 ± 1.79 5.16 ± 0.40 4.98 ± 0.13 Compound 7b (100 mg/kg) (Group 12) 41.54 ± 1.15a,b 7.12 ± 0.81a,b 6.78 ± 0.14a,b Compound 7b (200 mg/kg) (Group1 3) 39.17 ± 1.02a,b 6.82 ± 0.42a,b 6.18 ± 0.08a,b Vitamin E (100 mg/ kg) (Group 14) 45.17 ± 1.13 8.12 ± 0.11 7.37 ± 0.31 Values are mean ± SD, n = 6, a b the difference is significant (p>0.05) in a column between treated and untreated control group1. BREAK et al., Orient. J. Chem., Vol. 30(4), 1639-1645 (2014) 1641 4b and 5b respectively. In addition signals at 1625, with spin–spin coupling constant (J1',2') ranging from 1620 cm-1 for the C=N group of compounds 4a, 5a, 5.5-5 Hz for proton (H-1') assigned to the a - and at 1630 cm-1 of compounds 4b and 5b. anomeric configuration of compound 7a and 7b respectively. The IR spectra and the most important peaks for compounds (6a, 7a, 6b and 7b) were The 13C NMR spectrum of compounds observed at 3400-3450 cm”1 due to (OH group) (4a, b, 5a, b, 6a, b and 7a, b) showed the most for compounds 6a and 6b respectively and signals signals at C 13.4 and 18.6 for two groups of CH3 at 3380 cm-1 due to (OH group) for compounds 7a for compounds 4a and 5a. The five signals at C and 7b. 93.2, 84.2, 78.1, 71.4 and 59.2 were assigned to C-1', C-2' , C-3' , C-4', and C-5' of the sugar moiety, The 1H NMR spectra of compounds (4a, respectively. Data showed that at C 118.2 due to 5a, 4b and 5b) showed a doublet ranging from (CN), 120.0–135.0 (Ar), 151.2, 160.2, 168.0 (C=O); 5.55 - 6.39 ppm , with spin–spin coupling constant 175.0 (C=Se) of compound 4a and 175.9 (C=Se) ( 1',2') equal to 7.5 Hz for proton (H-1') which confirms of compound 4b. The 13C NMR spectrum of the -anomeric configuration of compound 4a and compounds 7a and 7b showed signals: 22.63, 4b respectively, while the data showed that a 29.70, 52.15, 63.42, 76.12, 79.11, 84.71, 117.786, doublet signals at ranging from 5.80 - 6.39 ppm , 128.39, 129.74, 132.09, 133.26, 169.79 for 7a and with spin–spin coupling constant (J1',2') ranging signals at 52.12, 64.50, 76.12, 79.11, 89.51, from 4.5-5 Hz for proton (H-1') assigned to the a - 117.53, 127.34, 128.28, 128.36, 128.65, 128.88, anomeric configuration of compound 5a and 5b 128.99, 129.57, 132.06, 132.92, 133.23, 134.13, respectively. 167.72, 169.27 for 7b The 1H NMR spectra of compounds (6a, Finally the Mass spectra and Elemental 7a, 6b and 7b) showed a doublet ranging analysis are in agreement and confirmed of all new compounds. From 6.20-6.08 ppm with (J1',2') equal to 7-7.5 Hz for for proton (H-1') which confirms the ²- Biological activity anomeric configuration of compound 6a and 6b. Toxicity studies While signals at 5ØÿÞ ranging from 6.08 - 6.22 ppm, Toxicity parameters including LD50; GPT Fig. 1: Effects of synthesized compounds on activities of GPT and LDH enzymes 1642 BREAK et al., Orient. J. Chem., Vol. 30(4), 1639-1645 (2014) and LDH activities were determined and ranged in diphenylpyridazine-4-carbonitrile (1a,b). Synthesis normal limits compared to infected untreated group of b and a-1-(2,3,5-tri-O-benzoyl--D-ribofuranosyl) with concentrations range up to 1000 mg kg- b.wt.