International Journal of Current Research and Review
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IJCRR - Vol 08 Issue 13, July, 2016

Pages: 42-49

Date of Publication: 12-Jul-2016


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SYNTHESIS AND APPLICATIONS OF SUGAR FLUORINATED NUCLEOSIDES

Author: Mohamed Ibrahim Elzagheid

Category: Healthcare

Abstract:In this review, different methods that have been used for the synthesis of 1'-, 2'-, 3'-, 4'- and 5'-sugar fluorinated nucleosides and their analogous are presented and different fluorinating agents are listed. Highlighted examples of the sugar fluorinated nucleosides that make a great impact on chemistry, biochemistry, and drug discovery are also elaborated. This review has shown that introduction of a fluorine atom in different positions within the sugar structure of the nucleoside improves their reactivity and properties.

Keywords: Nucleosides synthesis and applications, Sugar fluorinated nucleosides, Fluorinating agents

Full Text:

INTRODUCTION
Fluorinated nucleosides attracted many medicinal chemists because of their promising medicinal applications. They play a major role in interrupting the replication of cancer cells or viruses [1-3].A great intention was given by chemists to the introduction of fluoro group into sugars and nucleosides and different methods for the formation of fluorine carbon bond have been developed [4-7]. It is believed that the inherited biological activity of the fluorine incorporated nucleosides may be due to the electronegativity of fluorine and the strength of the carbon-fluorine bond. Strong electronic character of fluorine can alter the electronic properties of the nucleosides and induce interesting biophysical properties to the sugar-fluorinated nucleosides [8]. They can also be used as building blocks in oligonucleotides [9]. The synthesis of fluorinated nucleosides (by introduction of fluorine atom at 1’, 2’, 3’, 4’, and 5’ positions) can be achieved, by different fluorinating agents (Figure 1), through selective fluorination of nucleosides or by glycosylation of nucleic acids bases (nucleobases) with fluoro-sugar derivatives [10-14]. There are six reported methods for the synthesis of sugarfluorinated nucleosides (Figure 2). These are:

1. Epoxide cleavage by fluoride ions: This reaction has been used for the synthesis of 9-(3-deoxy-3-fluoro-β- D-xylofuranosyl) adenine 1 [15], and 9-(3-deoxy-3- fluoro-β-D-arabinofuranosyl) adenine 2 [16].

2. Displacement of sulfonyloxy group by fluoride ions: This reaction has been used for the synthesis of 5’-fluronucleosides because displacement of 5’-sulfonates with fluorine is more easily achieved than the same reaction with 2’- or 3’-sulfonates. A good example is the synthesis of 9-(3, 5-dideoxy-5-fluoro -β-D-ribofuranosyl) adenine 3 [17].

3. Fluorine anhydro ring opening: This reaction has also been used for the introduction of fluorine in 2’- and 3’-postitions: A good example is the synthesis of 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl) uracil 4 [18] and 1-(3-deoxy-3-fluoro-β-D-ribofuranosyl) uracil 5 [18].

4. One step exchange of hydroxyl group by fluorine: This has been achieved by treating desired sugar with diethylaminosulfurtrifluoride, DAST, or [bis (2-methoxyethyl)-amino] sulfurtrifluoride, MAST, then coupling the brominated fluorosugar with the nucleobases [10]. A good example is the synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) purine 6 [10].

5. Sequential photo-bromination and fluorination: In this method desired sugar was treated with N-bromosuccinimide, NBS, followed by fluorination with silver tetrafluoroborate (AgBF4 ) [19]. A good example here is the synthesis of 4’-fluoroadenosine 7.

6. Electrophilic fluorination of the nucleoside 1’-position: in this synthesis treatment of the 1’-lithium enolate, prepared from the 2’-ketoderivative, with N-fluorobenzenesulfonimide (NFSI) or 1-Chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (Selectfluor) , followed by reduction of the 2’-keto-moeity gave the 1’-fluorouridine derivatives [20, 21]. A good example is the synthesis of 1’-fluorouridine 8 (unprotected nucleosides was not successfully isolated because of the instability.

Although excellent reviews on the synthetic aspects of the fluorinated nucleosides have been published [12, 22],some of them were long and sometimes confusing. Our present review is short, clear and to the point. We tried here to put more emphasis on synthetic methodology and applications of the sugar fluorinated nucleosides.

DISCUSSION
1’- Fluorinated nucleosides
Almost all hydrogens attached to carbons have been substituted by fluorine atoms. However, substitution at 1’-carbon is rarely reported. This is may be due the feeling that 1’-nucleosides are difficult or unstable to synthesize. Recently the synthesis of protected 1’-fluoronucleosides (Scheme 1) was reported by Shuto group [20, 21]. In this synthesis, treatment of 2’-ketouridine 9 with Lithium bis (trimethylsilyl) amide (LiHMDS) and N-F fluorination agents such as Selectfluor or NFSI gave anomeric mixture of the 1’-fluoro-2’-ketouridine derivatives 10 and (Arabino type congener) in 57-88 % yield. Reduction of the 2’-keto group of 10 by diisobutylaluminiumhydride (DiBAL-H) followed by acetyl protection of the resulted hydroxyl group with acetic anhydride (Ac2 O) and 4-dimethylaminopyridine (DMAP) gave the 1’-fluorouridine derivatives 11 and 12 (8:9=1:4) in 68 % yield. This method has three drawbacks:

1. Only protected 1’-fluorouridine derivatives 11 and 12 were isolated and neither isolation nor deprotection and purification of the free 1’-fluoronucleoside was successful. This is may be due to the instability of the deprotected 1’-fluoruridine.

2. This method gives anomeric mixture of protected 1’-fluoruridines and that leads to low yield of the preferred β-anomer.

3. This method was not applied to purine nucleosides.

2’- Fluorinated nucleosides
More attention was given to the synthesis of 2’-β-Dfluoronucleosides (araF-nucleosides) over the 2’-α-D-fluoro nucleosides (riboF-nucleosides). This is because of the interesting antiviral activity shown by introducing a fluorine atom at the 2’-β-positions of the nucleosides and nucleoside analogs rather than at 2’-α-positions. Reichmann et al. [23] and Watanabe et al. [24] developed a synthetic method, in two steps, to obtain 2-deoxy-2-fluorD-arabinose 14a and 1-bromo-2-deoxy-2-fluoro-D-arabinose 14b from a readily available D-glucose derivative 13 (Scheme 2). Arabinose sugars 14a-b were used to synthesize series of fluorinated nucleosides 15-18 in a large scale for biological evaluation. Straightforward method for the synthesis of FIAC and FMAU nucleosides was also developed by Tann etal. [25]. For example, 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)- 5-iodocytosine (FIAC, 15), 1-(2-deoxy-2-fluoro-β-Darabinofuranosyl)-5-methyluracil (FMAU, 16), 1-(2-fluoro2-deoxy-β-D-arabinofuranosyl)-5-iodo uracil (FIAU, 17), and 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)-5-ethyl uracil (FEAU,18) have shown potent activity against Herpes Simplex Virus (HSV), and excellent activity against hepatitis-B virus (HBV) and cytomegalovirus (CMV). FMAU, 16 have also shown significant activity against murine leukemia [22]. Chu’s group [26, 27] has also reported an efficient procedure for the synthesis of 1- (2-deoxy-2-fluoro-β-Larabinofuranosyl)-5-methyluracil 21 from sugar 19 (Scheme 3). Another interesting approach is the synthesis of the 2’-fluorinated nucleosides, namely 2’-deoxy-2’-fluoro arabinonucleosides (araF-nucleosides) [28, 29]. They are used as building blocks for the synthesis of 2’-deoxy-2’-fluoro arabinonucleic acid (2’-F’ANA), [30-33] a very promising antisense oligonucleotides. Here the 2’-fluoro nucleosides were prepared via condensation of the silylated nucleic acids bases such as silylated N-acetyl cytosine or silylated thymine or N-benzoylated adenine with 2-deoxy-2-fluoro-3, 5-di-Obenzoyl-α-D-arabinofuranosyl bromide 22. Deprotection of the produced nucleosides, followed by 5’-tritylation and N-benzoylation give araF- nucleosides 23-25 in high yield (Scheme 4). The black sheep of this family of 2’-fluoro nucleosides is the 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) guanine (araFG) because the above mentioned procedure yields araF-G in low yields. An efficient synthesis of araF-G has been reported by Elzagheid et al. [29]. It involves coupling of 2-deoxy-2-fluoro-3, 5-di-O-benzoyl-α-D-arabinofuranosyl bromide 22 with silylated 2-chloro hypoxanthine 26 to afford 2-chloro-β-araF-I 27 that was transformed in araF-G 28 by treatment with methanolic ammonia in high yield (Scheme 5). Another efficient approach for the synthesis of araF-G 28 was reported by Sivets [34]. The synthesis involves reaction of potassium salts of 2-amino-6-chloropurine with 2-deoxy2-fluoro-3, 5-di-O-benzoyl-α-D-arabinofuranosyl bromide 22. In addition to methanolic ammonia, 2-mercaptoethanol and sodium methoxide in methanol was also used to convert the masked nucleoside to araF-G. In addition to the above mentioned syntheses, a novel synthesis and evaluation of the 5-ethyl analogs of the 2-deoxy-2-fluoro- β -D-arabinofuranosyl nucleosides was reported by Shakya et al. [35]. Among the tested fluorinated nucleosides, the 1-(3-bromo-2, 3-dideoxy-2-fluoro-β-Darabinofuranosyl)-5-ethyluracil has showed promising activity against Mycobacterium tuberculosis and Mycobacterium bovis with no cellular toxicity upto the highest concentration tested (CC50 > 100 µg/mL). A linear synthesis of 2’-deoxy-2’, 2’-difluorocytidine (Gemcitabine) was also reported by Brown et al. [36]. Gemcitabine under the trade name Gemzar, by Lilly Company, was widely used as anticancer drug. This linear synthesis involves conversion of 3, 5-di-O-benzoyl-2-deoxy-2, 2-difluororibose to corresponding glycosyl urea followed by conversion to cytosine base thru the uracil derivative.

3’- Fluorinated nucleosides
Carbon-3’-fluoronucleosides have shown a wide range of biological activity [37]. Among them, 3’-deoxy-3’-β-Dribofuranosides of adenine, guanine and their 2-deoxy analogs have shown potent antiviral and cytostatic activities [38]. Synthesis of 3’-fluorinatednucleosides such as 9-(3-deoxy3-fluoro-β-D-xylofuranosyl) adenine 1 [15] and 9-(3-deoxy3-fluoro-β-D-arabinofuranosyl) adenine 2 [16](Figure 2) by reacting 1-(5-O-benzoyl-2,3-epoxy-β-D-lyxofuranosyl) adenine with tetraethylammonium fluoride and 1-(5-O-benzoyl2,3-epoxy-β-D-ribofuranosyl) adenine with potassium hydrogen fluoride respectively are subject to few drawbacks. Vigorous reaction conditions are required for the ring opening and strictly anhydrous conditions are needed for the reagent and also to avoid formation of side products. Epoxide ring opening is relatively easy with HF in the presence of tetrahydrofuran or dioxane. This is because of the increased dissociation of the hydrofluoric acid [39]. An alternative route has been reported by Pankiewicz and Watanabe [40] for the synthesis of 9-(3-deoxy-3-fluoro-β- D-ribofuranosyl) adenine 33. This involves the treatment of the nucleoside triflate 29 with sodium acetate to give 3’-Oacetyl derivative 30. Mild hydrolysis of the later nucleoside in triethylamine-methanol-water mixture gave nucleoside 31 in good yield. Further treatment with DAST [(diethylaminosulfurtrifluoride, Et2 NSF3 ] gave the desired 3’-fluorosubstituted nucleoside 32 in high yield. Acidic treatment of 32 with acid gave nucleoside 33 (Scheme 6). Another interesting approach is the synthesis of 3’-fluorinated purine nucleosides 35-37 (Scheme 7) from 3’-fluorinated pyrimidine nucleosides 5 and 34 with the application of recombinant T. thermophilus pyrimidine nucleoside phosphorylase (TtpyNP) and E-Coli purine nucleoside phosphorylase (EcPNP) [41]. Another straightforward synthesis of 2’, 3’-dideoxy-3’- β-fluoronucleosides was reported by Khalil et al.42 The 5’-acetyl-3-nitro-2’-deoxynucleodies 38a-b were reacted with DAST in anhydrous dichloromethane-pyridine mixture to give the corresponding 3’- β -fluoronucleosides. Deprotection of the 3-nitro group was achieved by tributyltin hydride (Bu3SnH) in dry toluene in the presence of α, α’- azoisobutyronitrile (AIBN). Removal of the 5’-acetyl with methanolic ammonia afforded nucleosides 39a-b (Scheme 8).

4’- Fluorinated nucleosides
Another class of the fluoronucleosides that has attention of late is the 4’-fluoronucleosides. They are expected to have significant values in a variety of biochemical studies. A fruitful procedure has been reported by Lee et al. [19] where various 4’-fluorinated nucleosides 42-44 have been prepared in three steps via sequential bromination and fluorination of the ribofuranose 40. Glycosylation of the 4-fluoro-β-Dribofuranose 41 with N, O-bis-(trimethylsilyl) trifluoroacetamide and trimethylsilyl triflate followed by debenzoylation gave the desired fluoronucleosides in good yield (Scheme 9).

5’- Fluorinated nucleosides
Four approaches for the synthesis of 5’-fluoronucleosides 45-48 (Figure 3) have been reported. These include:

1. Nucleophilic displacement of sulfonates by fluoride ions: This reaction is carried out in either mesylates or tosylates with potassium fluoride in ethylene glycol or with tetrabutylammonium fluoride in dimethylformamide (DMF). However, the use of hydrofluoric acid in dioxane has been reported to give better yields [17].

2. Opening of the O2 , 5’-bond of anhydronucleosides: these anhydronucleosides can serve as good starting materials but they are rarely used [43].

3. Reaction of a free 5’-hydroxyl group with DAST. This reagent has been successfully applied for the replacement of hydroxyl group by a fluorine atom [44].

4. Displacement of iodine as leaving group: In this approach silver fluoride in pyridine has been used for introduction of fluorine atom at 5’-position of the 5’-iodouridine [14].

CONCLUSIONS
In this review, a highlighted number of important synthetic methods of biologically active fluorinated nucleosides have been covered. A fluorine atom, as a mimic of hydrogen or hydroxyl group, that has been introduced in different positions in the sugar moiety of the nucleoside has surely improved their pharmacological and biological properties.

ACKNOWLEDGMENT
Author acknowledges the immense help received from the scholars whose articles are cited and included in references of this manuscript. The author is also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.

References:

1. Turner M A, Yang X, Yin D, Kuczera K, Borchardt R T, Howell P L. Structure and function of S-adenosylhomocysteine hydrolase. Cell Biochem Biophys 2000; 33: 101-125.

2. Kitade Y, Kozaki C, Miwa T, Nakanishi M. Synthesis of basemodified noraristeromycin derivatives and their inhibitory activity against human and plasmodium falciparum recombinant S-adenosylhomocysteine hydrolase. Tetrahedron 2002; 58: 1271-1277.

3. Anderson K S. Perspectives on the molecular mechanism of inhibition and toxicity of nucleoside analogs that target HIV-1 reverse transcriptase. Biochimica et Biophysica Acta 2002; 1587: 296-299.

4. Welch J T. Advances in the preparation of biologically active organofluorine compounds. Tetrahedron 1987; 43 (14): 3123- 3197.

5. Wilkinson J A. Recent advances in the selective formation of the carbon-fluorine bond Chem Rev 1992; 92 (4): 505-519.

6. Purrington S T, Kagen B S, Patrick T B. Application of elemental fluorine in organic synthesis. Chem Rev 1986; 86 (6): 997- 1018.

7. Schlosser M. Introduction of fluorine into organic molecules: why and how. Tetrahedron 1978; 34 (1): 3-17.

8. Ma T, Lin J-S, Gary N M, Cheng Y-C, Chu C K. Synthesis and anti-hepatitis B virus activity of 9-(2-deoxy-2-fluoro-β-larabinofuranosyl) purine nucleosides. J Med Chem 1997; 40: 2750–2754.

9. Kalota A, Karabon L, Swider CR, Viazovkina E, Elzagheid MI, Damha MJ, and Gewirtz AM. 2’-Deoxy-2’-fluoro-β-Darabinonucleic acid (2’F-ANA) modified oligonucleotides (ON) effect highly efficient, and persistent, gene silencing. Nucleic Acids Research 2006; 34 (2): 451–461.

10. Takamatsu S, Katayama S, Hirose N, De Cock E, Schelkens G, Demillequand M, Brepoels J, and Izawa K. CONVENIENT SYNTHESIS OF FLUORINATED NUCLEOSIDES WITH PERFLUOROALKANESULFONYL FLUORIDES. Nucleosides Nucleotides and Nucleic Acids 2002; 21(11-12):849-861.

11. Yamada K, Matsumoto N, and Hayakawa H. Stereoselective Synthesis of 2-Deoxy-2-Fluoroarabinofuranosylα-1-Phosphate and Its Application to the Synthesis of 2′-Deoxy-2′-Fluoroarabinofuranosyl Purine Nucleosides by a Chemo-Enzymatic Method. Nucleosides Nucleotides and Nucleic Acids 2009; 28 (11-12): 1117-1130.

12. Pankiewicz K W. Fluorinated nucleosides. Carbohydr Res 2000; 327: 87-105.

13. Kodama T, Matsuda A, Shuto S. The first synthesis of 1’-fluoronucleosdies. Nucleic Acids Symposium Series 2006; 50: 3-4.

14. Herdewijn P, Van Aerschot A, Kerremans L. Synthesis of nucleosides fluorinated in the sugar moiety. The application of diethylaminosulfur trifluoride to the synthesis of fluorinated nucleosides. Nucleosides, Nucleotides 1989; 8(1): 65-96.

15. Robins M J, Fouron Y, Mengel R. Adenosine 2′, 3′-ribo-epoxide. Synthesis, intramolecular degradation, and transformation into 3′-substituted xylofuranosyl nucleosides and the lyxo-epoxide. J Org Chem 1974; 39: 1564-1570.

16. Miyai K, Robins RK, Tolman RL. Synthesis of 9-(3-deoxy-3- fluoro-β-D-arabinofuranosyl) adenine. J Med Chem 1972; 15: 1092-1994.

17. Kissman HM, Weiss MJ. 5-Deoxy-5-fluoro-D-ribofuranosyl Derivatives of Certain Purines, Pyrimidines and 5, 6-Dimethylbenzimidazole. J Am Chem Soc 1958; 80 (20): 5559–5564.

18. Kowollik G, Gaertuer K, Langen P. Nucleosides of fluorocarbohydrates. XIII. Synthesis of 3’ deoxy 3’ fluorouridine. J. Carbohydr Nucl Nucl 1975; 2 (3): 191-195.

19. Lee S, Uttamapinant C, Verdine G L. A concise synthesis of 4’-fluoronucleosides. Org Lett 2007; 9 (24): 5007-5009. And references therein.

20. Kodama T, Matsuda A, Shuto S. Synthesis of 1’-fluorouracil nucleosides as potential antimetabolites. Tetrahedron 2006; 62: 10011-10017.

21. Kodama T, Shuto S, Matsuda A. Synthesis of pyrimidine 1’-fluoronucleosides. Tetrahedron Lett 2006; 47: 4429-4432.

22. Liu P, Sharon A, Chu CK. Fluorinated nucleosides. J Fluor Chem 2008; 129 (9): 743-766.

23. Reichmann U, Watanabe KA, Fox JJ. A practical synthesis of 2-deoxy-2-fluoro-D- arabinofuranose derivatives. J Carbohydr Res 1975; 42 (2): 233-240.

24. Watanabe KA, Su TL, Klein RS, Chu CK, Matsuda A, Chun MW, Lopez C, Fox JJ. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-β-D-arabinofuranosyl) cytosine and -uracil. Some structure-activity relationships. J Med Chem 1983; 26 (2): 152-156.

25. C. H. Tann, P. R. Brodfuehrer, S. P. Brundidge, C. Sapino, H. G. Howell, Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil (β-FIAU) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) thymine (β -FMAU). J Org Chem 1985; 50: 3644-3647.

26. Ma T, Pai SB, Zhu XL, Lin JS, Shanmu K, Du J, Wan C, Kim H, Newton MG, Cheng YC, Chu CK. Structure--activity relationships of 1-(2-Deoxy-2-fluoro-β-L arabinofuranosyl)pyrimidine nucleosides as anti-hepatitis B virus agents. J Med Chem 1996; 39 (14): 2835-2843.

27. Du J, Choi Y, Lee K, Chun BK, Hong JH, Chu CK, A Practical Synthesis of L-FMAU from L-Arabinose. Nucleosides Nucleotides 1999; 18: 187-192.

28. Elzagheid M I, Viazovkina E, Damha M J. Synthesis of protected 2’-deoxy-2’-fluoro-β-D-arabinonucleosides.Current Protocols in Nucleic Acid Chemistry 2002; 1.7.1–1.7.19. And references therein.

29. Elzagheid M I, Viazovkina E, Damha M J. A new synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) guanine. Nucleosides, Nucleotides and Nucleic Acids 2003; 22: 1339-1342. And references therein.

30. Damha M J, Wilds C J, Noronha A, Brunker I, Brokow G, Arion D, Parniak M A. Hybrids of RNA and arabinonucleic acids (ANA and 2’F-ANA) are substrates of ribonuclease H. J AmChem Soc 1998; 120 (49): 12976-12977.

31. Wilds C J, Damha M J. 2’-Deoxy-2’-fluoroarabinonucleosides and oligonucleotides (2’F-ANA): synthesis and physicochemical studies. Nucleic Acids Res 2000; 28: 3625–3635.

32. Lok C N, Viazovkina E, Min K L, Nagy E, Wilds C J, Damha M J, Parniak M A. Potent gene-specific inhibitory properties of mixed-backbone antisense oligonucleotides comprised of 2’-deoxy-2’-fluoro-D-arabinose and 2’-deoxyribose nucleotides. Biochemistry 2002; 41 (10): 3457-3467.

33. Viazovkina E, Mangos M M, Elzagheid M I, Damha M J. solid-phase synthesis of 2′-Deoxy-2′-fluoro-β-Doligoarabinonucleotides (2′F-ANA) and their phosphorothioate derivatives. Current Protocols in Nucleic Acid Chemistry 2002; 4.15.1-4.15.22.

34. Sivets G G. Syntheses of 2’-deoxy-2’-fluoro-β-Darabinofuranosyl purine nucleosides via selective glycosylation reactions of potassium salts of purine derivatives with glycosyl bromide. Tetrahedron Lett 2016; 57: 268-271.

35. Shakya N, Srivastav N C, Bhavanam S, Tse C, Desroches N, Agrawal B, Kunimoto D Y, and R. Kumar R. Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2’-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis Mycobacterium bovis and Mycobacterium Avium inhibitors. Bioorganic and Med Chem 2012; 20: 4088-4097.

36. Brown K, Weymouth-Wilson A, and Linclau B. A linear synthesis of gemcitabine. Carbohydrate Res 2015; 406: 71-75.

37. Qui X-I, Xu X-H, and Qing F-L. Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 2010; 66: 789-843.

38. Mikhailopulo I A, Poopeiko N E, Prikota T I, Sivets G G, Kvasyuk E I, Balzarini J, De Clercq E. Synthesis and antiviral and cytostatic properties of 3′-deoxy-3′-fluoro- and 2′-azido-3′-fluoro2′,3′-dideoxy-D-ribofuranosides of natural heterocyclic bases. J Med Chem 1991; 34 (7): 2195-2202.

39. Hirschman R E, Miller R, Wood J, Jones R E. The Reaction of Epoxides with Anhydrous Hydrogen Fluoride in the Presence of Organic Bases. The Preparation of 9-α-Fluoro-4-pregnene-11β, 17α, 21-Triol 3, 20-Dione 21-Acetate and Its 1-Dehydro Analog. J Am Chem Soc 1956; 78 (19): 4956-4959.

40. Pankiewicz K W, and Watanabe K A. A synthesis of 2’-fluoroand 3’-fluoro-substituted purine nucleosides via a direct approach. Nucleosides and Nucleotides as Antitumor and Antiviral Agents, Plenum Press, New York, 1993; 55-71.

41. D. V. Burko, Biotechnology in Medicine, Food Stuffs, Biocatalysis, Environment and Biogeotechnology, eds S. D. Varfolomeev, G. E. Zaikov, L. P. Krylova. Nova Science Publisher, New York, 2010; 1-13.

42. Khalil A, Mathe C, and Perigaud C. Rapid synthesis of 2’,3’-dideoxy-3’-β-fluoro-pyrimidine nucleosides. Bioorganic Chem 2010; 38: 271-274.

43. Kowollik G, Schutt M, Langen P, Demirow G. Nucleoside von Fluorzuckern; Synthese der 5′-Desoxy-5′-fluor-Derivate von 6-Aza-uridin und Ribofuranosyl-thymin. Z Chem 1972; 12 (3): 106-107.

44. Middleton W J. New fluorinating reagents. Dialkylaminosulfur fluorides. J Org Chem, 1975; 40 (5): 574-578.







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A Study by Mbungu Mulaila AP et al. entitled "Ovarian Pregnancy in Kindu City, D.R. Congo - A Case Report" is awarded Best Article for Vol 14 issue 03
A Study by Maryam MJ et al. entitled "Evaluation Serum Chemerin and Visfatin Levels with Rheumatoid Arthritis: Possible Diagnostic Biomarkers" is awarded Best Article for Vol 14 issue 02
A Study by Shanthan KR et al. entitled "Comparison of Ultrasound Guided Versus Nerve Stimulator Guided Technique of Supraclavicular Brachial Plexus Block in Patients Undergoing Upper Limb Surgeries" is awarded Best Article for Vol 14 issue 01
A Study by Amol Sanap et al. entitled "The Outcome of Coxofemoral Bypass Using Cemented Bipolar Hemiarthroplasty in the Treatment of Unstable Intertrochanteric Fracture of Femur in a Rural Setup" is awarded Best Article Award of Vol 13 issue 24
A Study by Manoj KP et al. entitled "A Randomized Comparative Clinical Trial to Know the Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block Against Multimodal Analgesia for Postoperative Analgesia Following Caesarean Section" is awarded Best Article Award of Vol 13 issue 23
A Study by Karimova II et al. entitled "Changes in the Activity of Intestinal Carbohydrases in Alloxan-Induced Diabetic Rats and Their Correction with Prenalon" is awarded Best Article of Vol 13 issue 22
A Study by Ashish B Roge et al. entitled "Development, Validation of RP-HPLC Method and GC MS Analysis of Desloratadine HCL and It’s Degradation Products" is awarded Best Article of Vol 13 issue 21
A Study by Isha Gaurav et al. entitled "Association of ABO Blood Group with Oral Cancer and Precancer – A Case-control Study" is awarded Best Article for Vol 13 issue 20
A Study by Amr Y. Zakaria et al. entitled "Single Nucleotide Polymorphisms of ATP-Binding Cassette Gene(ABCC3 rs4793665) affect High Dose Methotrexate-Induced Nephrotoxicity in Children with Osteosarcoma" is awarded Best Article for Vol 13 issue 19
A Study by Kholis Ernawati et al. entitled "The Utilization of Mobile-Based Information Technology in the Management of Dengue Fever in the Community Year 2019-2020: Systematic Review" is awarded Best Article for Vol 13 issue 18
A Study by Bhat Asifa et al. entitled "Efficacy of Modified Carbapenem Inactivation Method for Carbapenemase Detection and Comparative Evaluation with Polymerase Chain Reaction for the Identification of Carbapenemase Producing Klebsiella pneumonia Isolates" is awarded Best Article for Vol 13 issue 17
A Study by Gupta R. et al. entitled "A Clinical Study of Paediatric Tracheostomy: Our Experience in a Tertiary Care Hospital in North India" is awarded Best Article for Vol 13 issue 16
A Study by Chandran Anand et al. entitled "A Prospective Study on Assessment of Quality of Life of Patients Receiving Sorafenib for Hepatocellular Carcinoma" is awarded Best article for Vol 13 issue 15
A Study by Rosa PS et al. entitled "Emotional State Due to the Covid – 19 Pandemic in People Residing in a Vulnerable Area in North Lima" is awarded Best Article for Vol 13 issue 14
A Study by Suvarna Sunder J et al. entitled "Endodontic Revascularization of Necrotic Permanent Anterior Tooth with Platelet Rich Fibrin, Platelet Rich Plasma, and Blood Clot - A Comparative Study" is awarded Best Article for Vol 13 issue 13
A Study by Mona Isam Eldin Osman et al. entitled "Psychological Impact and Risk Factors of Sexual Abuse on Sudanese Children in Khartoum State" is awarded Best Article for Vol 13 issue 12
A Study by Khaw Ming Sheng & Sathiapriya Ramiah entitled "Web Based Suicide Prevention Application for Patients Suffering from Depression" is awarded Best Article for Vol 13 issue 11
A Study by Purushottam S. G. et al. entitled "Development of Fenofibrate Solid Dispersions for the Plausible Aqueous Solubility Augmentation of this BCS Class-II Drug" is awarded Best article for Vol 13 issue 10
A Study by Kumar S. et al. entitled "A Study on Clinical Spectrum, Laboratory Profile, Complications and Outcome of Pediatric Scrub Typhus Patients Admitted to an Intensive Care Unit from a Tertiary Care Hospital from Eastern India" is awarded Best Article for Vol 13 issue 09
A Study by Mardhiah Kamaruddin et al. entitled "The Pattern of Creatinine Clearance in Gestational and Chronic Hypertension Women from the Third Trimester to 12 Weeks Postpartum" is awarded Best Article for Vol 13 issue 08
A Study by Sarmila G. B. et al. entitled "Study to Compare the Efficacy of Orally Administered Melatonin and Clonidine for Attenuation of Hemodynamic Response During Laryngoscopy and Endotracheal Intubation in Gastrointestinal Surgeries" is awarded Best Article for Vol 13 issue 07
A Study by M. Muthu Uma Maheswari et al. entitled "A Study on C-reactive Protein and Liver Function Tests in Laboratory RT-PCR Positive Covid-19 Patients in a Tertiary Care Centre – A Retrospective Study" is awarded Best Article of Vol 13 issue 06 Special issue Modern approaches for diagnosis of COVID-19 and current status of awareness
A Study by Gainneos PD et al. entitled "A Comparative Evaluation of the Levels of Salivary IgA in HIV Affected Children and the Children of the General Population within the Age Group of 9 – 12 Years – A Cross-Sectional Study" is awarded Best Article of Vol 13 issue 05 Special issue on Recent Advances in Dentistry for better Oral Health
A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" is awarded Best Article of Vol 13 issue 06
A Study by Chen YY and Ghazali SRB entitled "Lifetime Trauma, posttraumatic stress disorder Symptoms and Early Adolescence Risk Factors for Poor Physical Health Outcome Among Malaysian Adolescents" is awarded Best Article of Vol 13 issue 04 Special issue on Current Updates in Plant Biology to Medicine to Healthcare Awareness in Malaysia
A Study by Kumari PM et al. entitled "Study to Evaluate the Adverse Drug Reactions in a Tertiary Care Teaching Hospital in Tamilnadu - A Cross-Sectional Study" is awarded Best Article for Vol 13 issue 05
A Study by Anu et al. entitled "Effectiveness of Cytological Scoring Systems for Evaluation of Breast Lesion Cytology with its Histopathological Correlation" is awarded Best Article of Vol 13 issue 04
A Study by Sharipov R. Kh. et al. entitled "Interaction of Correction of Lipid Peroxidation Disorders with Oxibral" is awarded Best Article of Vol 13 issue 03
A Study by Tarek Elwakil et al. entitled "Led Light Photobiomodulation Effect on Wound Healing Combined with Phenytoin in Mice Model" is awarded Best Article of Vol 13 issue 02
A Study by Mohita Ray et al. entitled "Accuracy of Intra-Operative Frozen Section Consultation of Gastrointestinal Biopsy Samples in Correlation with the Final Histopathological Diagnosis" is awarded Best Article for Vol 13 issue 01
A Study by Badritdinova MN et al. entitled "Peculiarities of a Pain in Patients with Ischemic Heart Disease in the Presence of Individual Combines of the Metabolic Syndrome" is awarded Best Article for Vol 12 issue 24
A Study by Sindhu Priya E S et al. entitled "Neuroprotective activity of Pyrazolone Derivatives Against Paraquat-induced Oxidative Stress and Locomotor Impairment in Drosophila melanogaster" is awarded Best Article for Vol 12 issue 23
A Study by Habiba Suhail et al. entitled "Effect of Majoon Murmakki in Dysmenorrhoea (Usre Tams): A Standard Controlled Clinical Study" is awarded Best Article for Vol 12 issue 22
A Study by Ghaffar UB et al. entitled "Correlation between Height and Foot Length in Saudi Population in Majmaah, Saudi Arabia" is awarded Best Article for Vol 12 issue 21
A Study by Siti Sarah Binti Maidin entitled "Sleep Well: Mobile Application to Address Sleeping Problems" is awarded Best Article for Vol 12 issue 20
A Study by Avijit Singh"Comparison of Post Operative Clinical Outcomes Between “Made in India” TTK Chitra Mechanical Heart Valve Versus St Jude Mechanical Heart Valve in Valve Replacement Surgery" is awarded Best Article for Vol 12 issue 19
A Study by Sonali Banerjee and Mary Mathews N. entitled "Exploring Quality of Life and Perceived Experiences Among Couples Undergoing Fertility Treatment in Western India: A Mixed Methodology" is awarded Best Article for Vol 12 issue 18
A Study by Jabbar Desai et al. entitled "Prevalence of Obstructive Airway Disease in Patients with Ischemic Heart Disease and Hypertension" is awarded Best Article for Vol 12 issue 17
A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09

List of Awardees

A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award


A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award


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International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal

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