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into into der
niik
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tartışılmıştır. tartışılmıştır.
10% 10%
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toothbrush, toothbrush,
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TURKEY TURKEY
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REVIEWS REVIEWS
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2001 2001
compounds compounds
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promising promising
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129-136, 129-136,
Anti·hepatitis Anti·hepatitis
only only
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Aııti-Hepavtis Aııti-Hepavtis
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which which
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0 0
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Sci., Sci.,
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Ankara, Ankara,
in in
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agents. agents.
nucleoside nucleoside
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alphabetica! alphabetica!
hepatitis hepatitis
(HBV) (HBV)
Nııcleosides, Nııcleosides,
fection fection
these these
of of
15.5.2001 15.5.2001
28.6.2001 28.6.2001
27.6.2001 27.6.2001
family. family.
the the
morbidity morbidity
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there there
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of of
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role role
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initials: initials:
: :
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intent intent
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Nucleosides Nucleosides
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inflammation inflammation
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virus virus
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Words: Words:
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Correspondence Correspondence
University University
fact fact
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the the separate separate
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treatment treatment
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alsa alsa
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1987, 1987,
tissue tissue
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can can
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130 130 Öl Öl
shorter shorter
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J. is is 2. 2. retroviruses, retroviruses, the the = = =OH. =OH. many many = = carbocyclic carbocyclic l'-<:llG l'-<:llG anti-HBV anti-HBV synthesized synthesized anti-HBV anti-HBV found found X X X X X X 3'-Dideoxy 3'-Dideoxy the the an an culture culture deoxythymidine), deoxythymidine), tential tential of of was was Transcriptase) Transcriptase) tion, tion, 2', 2', Since Since nucleosides nucleosides Figure Figure Recently, Recently, erate erate been been activity activity 200475 200475 reported reported portant portant as as cyclobutyl cyclobutyl reported reported novel novel deoxyguanosine deoxyguanosine Figure Figure Several Several FABAD FABAD exhibiting exhibiting nucleoside nucleoside it it t it it it it is is an an in in an an re be be D he re en !he !he the the ad and and be cul na na Bio also also sub clin as as com as as Blood Blood and and (P-2,6- DAPD DAPD and and under- T-cells T-cells can can FTC FTC DHBV DHBV activity activity of of exhibit exhibit the the cells)34. cells)34. celi celi the the µM) µM) nor nor in in The The towards towards whu whu Cytidine Cytidine generally generally favorable favorable is is cells) cells) FTC FTC of of adenosine adenosine to to in in in in approved approved levels levels good good L-isomer. L-isomer. a a !hat !hat in in L-(-)-OddC L-(-)-OddC L-(-)-OddC L-(-)-OddC Recently, Recently, either. either. trials trials respectively] respectively] O.Ol O.Ol degrades degrades are are by by 2.2.15 2.2.15 cif cif (DXG), (DXG), patent patent phase-lll phase-lll the the PBM PBM 50 50 been been developed developed L-isomer L-isomer 7). 7). with with nota nota DAPD DAPD in in (deoxy (deoxy growth growth DAPD DAPD patients patients shown shown function. function. moiety moiety L-isomer L-isomer in in (Peripheral (Peripheral patients patients activity activity !hat !hat ducks33. ducks33. 2,6-diarninopurine 2,6-diarninopurine (Human (Human is is ~-L-isomer ~-L-isomer results results L-isomers L-isomers cells, cells, (EC vivo vivo the the which which !han !han clinical clinical dose-dependent dose-dependent nM nM indicated indicated replication replication structure-activity structure-activity gar gar D-, D-, cells) cells) L-isomer. L-isomer. µM µM the the HBV-DNA HBV-DNA the the being being the the dCK dCK been been the the as as exhibits exhibits in in il il and and AIDS AIDS and and su su PBM PBM Additionally, Additionally, recently recently 0.5 0.5 discovery discovery (Figure (Figure vitro vitro rate rate is is the the any any of of cells) cells) D D cytotoxicity, cytotoxicity, the the the the by by !he !he tumors tumors of of 50 50 has has 0.03 0.03 in in undergoing undergoing anti-HIV anti-HIV !hat !hat the the CEM CEM in in infected infected has has 2.2.15 2.2.15 of of the the studies studies Currently, Currently, enzymes enzymes agent. agent. the the 50 50 is is DXG DXG 7), 7), patent patent phase phase (EC DAPD DAPD P-D-isomer P-D-isomer 70% 70% in in to to nM nM show show deaminase, deaminase, trial, trial, currently currently higher higher inhibits inhibits Extensive Extensive DAPD DAPD mitochondrial mitochondrial 3TC 3TC with with as as to to (EC 5 5 dioxolane-guanine dioxolane-guanine in in and and neither neither is is the the lines31,32. lines31,32. patent patent led led µM µM and and prostate prostate activity activity cytosine) cytosine) it it the the Animal Animal of of potency potency Leukemia Leukemia not not treatment treatment dioxolanes) dioxolanes) significant significant (Figure (Figure to to inhibition between between suggested suggested and and activity activity celi celi much much anti-HBV anti-HBV catabolic catabolic !hat !hat AZT AZT 0.09 0.09 clinical clinical HIV36 HIV36 on on dose30. dose30. and and cytidine cytidine (±)-FTC (±)-FTC cluonically cluonically 2 2 a a the the (ADA)38,39. (ADA)38,39. agent35. agent35. was was an an treat, treat, 50 50 ll ll agent. agent. analogue analogue studies studies phosphorylated phosphorylated undergoing undergoing of of at at 50 50 and and the the mg mg in in show show converted converted as as to to for for with with However, However, extremely extremely profile. profile. both both strong strong L-(-)-OddC L-(-)-OddC (EC antiviral antiviral prodrug prodrug studies studies anti-HBV anti-HBV 25 25 [EC 7 7 effects effects for for undetectable undetectable be be 3 (cis-5-fluoro-l-[2-(hydroxymethyl)-1,3-oxathiolan (cis-5-fluoro-l-[2-(hydroxymethyl)-1,3-oxathiolan D-configuration. D-configuration. reported reported difference difference anti-HBV anti-HBV not not phase phase hepatoma hepatoma lrials lrials vivo vivo the the FDA FDA al al 5-yl]-cytosine) 5-yl]-cytosine) toxicity toxicity dearninase dearninase HBV dioxolane dioxolane can can ur ur against against is is difficult difficult anti-cancer anti-cancer patocellular patocellular Lymphoblastic Lymphoblastic P-L-dioxolane P-L-dioxolane Since Since and and exhibits exhibits Mononuclear) Mononuclear) diaminopurine diaminopurine tures tures lationship lationship anti-HBV anti-HBV currently currently racemate racemate anabolic anabolic was was verse verse Kinase). Kinase). This This hanced hanced D-isomer D-isomer efficient!y efficient!y strate strate did did enantiomer enantiomer logical logical the the in in showed showed cent cent FTC, FTC, polen! polen! ceived ceived ical ical bination bination carne carne - by by in in L el el re- in lri (2' Nllı Nllı a a Un (100 (100 !hat !hat may may with with fluo arab HBV HBV [(-)-P com arab poly shown shown X"' X"' in in at at HBV HBV HlV HlV reduced reduced L- 9. 9. All All and and L- Olgen, Olgen, OH OH 2 3TC 3TC DArl>, DArl>, DXG,X.,,011 DXG,X.,,011 derivatives derivatives The The been been DNA DNA and and endogenous endogenous FIACTP FIACTP with with and and suggests suggests against against form form cytosine cytosine and and ':Z ':Z ~ ~ activity activity rapidly rapidly slructures. slructures. effects L~-o.__JoH L~-o.__JoH nucleosides nucleosides also also combined combined L- D- 6). 6). vira! vira! compounds compounds activity, activity, ducks ducks of of of of has has inhibit inhibit ( ( which which 3TC 3TC - D in in nucleosides. nucleosides. was was Y Y irnidazole irnidazole X X N nucleosides, nucleosides, patients patients imidazoles imidazoles to to B, B, nucleosides nucleosides activities activities adverse adverse class class ln ln !eve! !eve! inhibition inhibition {-)-Odd(' {-)-Odd(' dioxolane dioxolane and and and and irnidazole irnidazole (Figure (Figure these these characlerized, characlerized, anti-HBV anti-HBV DHBV DHBV the the activity, activity, !his !his 7)28. 7)28. and and shown shown 50% 50% at at and and of of serious serious hepatitis hepatitis y y glycoside glycoside vitro vitro well well synthesized synthesized about about arabinofuranosyl arabinofuranosyl 2'-deoxy-2'-fluoro 2'-deoxy-2'-fluoro no no significant significant agents agents been been J J dioxolane dioxolane part, part, the the not not N N X (Figure (Figure itsin itsin suppress suppress shown shown activity activity 1,2,3-triazole 1,2,3-triazole in in 1,2,3-triazole 1,2,3-triazole no no z: z: with with lriazole lriazole fom1 fom1 is is chronic chronic 2'-deoxy-2'-fluoro 2'-deoxy-2'-fluoro for for to to has has HBV. HBV. polymerase polymerase findings findings O- Oxathiolane Oxathiolane 5-iodo 5-iodo 6. 6. have have and and OH OH of of 7. 7. ~ ~ FTC.X=F FTC.X=F JTC.X=li JTC.X=li found found DNA DNA synthesized synthesized anti-HBV anti-HBV againsl againsl anti-HBV anti-HBV effectively effectively addition addition mediated, mediated, view view HO\_,_o-~J HO\_,_o-~J 132 132 to to HBV-DNA HBV-DNA L-2',3'-dideoxy-3'-thiacyctidine] L-2',3'-dideoxy-3'-thiacyctidine] fection fection chimpanzees chimpanzees in in Figure Figure Oxathiolane, Oxathiolane, nucleosides nucleosides Figure Figure inofuranosyl inofuranosyl µM µM fortunately, fortunately, pounds pounds were were heterocyclic heterocyclic roarabinofuranosyl roarabinofuranosyl aJ.27, aJ.27, the the as as inofuranosyl inofuranosyl merase26. merase26. fluoro, fluoro, Ölgen Ölgen in in HBV HBV compounds compounds phosphale) phosphale) be be FABAD J. Pharın.Sci .. 26, 129-136. 2001 going preclinical studies as an anti-HIV and anti was no inhibitory effect on HBV transcription or pro HBV agent. tein synthesis. L-FMAU was faund !o be metabolized in cells by the cellular thymidine kinase and deoxy The interesting findings !hat some of the nucleosides citidine kinase to its monophosphate, and sub with unnatural L-configuration show more polen! sequently to the di- and triphosphate by some other antiviral activity with lower cytoxicity !han cor unknown enzymes (Figure 9). responding D-counterparts led to the extensive lnhibitionof HBV and EBV j screening of L-nucleosides (Figure 8) as potential an l DNA polymerases tiviral agents. In this regard, several new anti-HBV agents have been discovered. TK L-FMAU ~ l-FMAUMP -- L-FMAUOP - L-FMAUTP klnase human ONA polymerases t a. p, ôand ONA ' 1.- The L-enantiomer of the anti-HIV drug ddC was re mltochondrlal compartment mi-ONA ported to exhibit polen! anti-HBV activity (EC50 O.Ol µM, 2.2.15 cells). Its 5-fluoro congener (L-FddC) (Fig Figure 9. Proposed metabolism of L-FMAU46 ure 8) showed not only potent anti-HBV activity (EC50 O.Ol µM) but also potent anti-HIV activity Although the precise mechanism of action of L without significant toxicity in celi cultures40,41. Re FMAU is not clear, a dose-dependent inhibition of cently, L-FddC has also been shown to be a strong in HBV DNA synthesis by L-FMAUTP (L-5-methyl-2- 4 hibitor of DHBV both in vitro and in vivo 2. Two oth fluoro arabinofuranosyl uracil triphosphate) was ob er L-nucleosides, namely L-Fd4C (L-2'-fluoro-2',3' served in the DNA polymerase assays with isolated dideoxycytosine) and L-d4C (L-2',3'-didehydro-2',3' HBV particles, suggesting that inhibition of vira! dideoxycytosine) (Figure 8) have alsa been reported DNA polymerase may account far its anti-HBV activ to have patent antiviral activities43. L-Fd4C shows ity. extremely polen! anti-HBV activity (EC50 2 nM in 2.2.15 cells) and anti-HIV activity (EC 0.09 µM in 50 In addition lo its in vitro anti-HBV activity, L-FMAU CEM cells), whereas L-d4C is less poleni against both also exhibits potent activity against DHBV in prirnary viruses (8 nM and 1.0 µM far HBV and HIV, re duck hepatocytes (EC 0.1 µM)47,48. The phar spectively). 50 macokinetics of L-FMAU in rats have been reported by Wright et al.49. A linear disposition of L-FMAU, Another L-nucleoside, L-FMAU [1-(2-fluoro-5- was observed over the dosage of 10 to 50 mg/kg after methyl-~-L-arabinofuranosyl)uracil],(Figure 8) was intravenous administration. L-FMAU with these out reported by Chu et al. 44, as a patent antiviral agent standing features, is considered as a promising clinical against HBV (EC50 0.1 µM in 2.2.15 cells). L-FMAU was faund to have a low cytotoxicity while the D agent for the treatment of chronic HBV infectionsso. counterpart, D-FMAU, was determined to be less ac tive and significantly more toxic. In addition to its Recently, a different class, of nucleoside containing patent anti-HBV activity, L-FMAU alsa exhibits po the iınidazo[4, 5-e] [l, 3] diazepine heterocyclic ring tent anti-EBV activity. The anti-HBV mechanism of system was also reported by Chen et al. 51. Among the L-FMAU has been reported by Pai et al.45. it was synthesized nucleosides, 6-amino-8-hydroxy-4H-1-P found !hat L-FMAU produced a dose-dependent in D-ribofuranosylirnidazo[ 4,5-e] [l,3] diazepine-4-one hibition to the vira! DNA replication in 2.2.15 cells was found to be a potent anti-hepatitis B virus agent with a 50% inhibitory concentration at 0.1 µM. There (Figure 10). 133 . . . . ,. ,. . . [ [ :. :. B B ]. ]. S, S, R. R. R, R, Y, Y, of of Z, Z, 2' B, B, an an vi 2L 2L 84, 84, cir line line C C that that Pro 2',3' anti Natl. Natl. Proc. Proc. 8541- in in poly Paris, Paris, (1&2), (1&2), 1988. 1988. Chem. Chem. cloned cloned experi human human expres replica activity activity Res. Res. Shapiro Shapiro Park Park of of cultures cultures M. M. cell cell Chu Chu 86, 86, DNA, DNA, USA, USA, compari 19 19 cells cells 1986. 1986. chronic chronic R, R, Innaimo Innaimo hepatitis hepatitis Proc. Proc. Replicative Replicative transfected transfected cloned cloned the the A A Colonno Colonno hepatitis hepatitis analogue analogue with with Merchant Merchant Med. Med. Yarchoan Yarchoan vitro vitro Nucleosides, Nucleosides, YC, YC, Sci. Sci. of of AM, AM, of of selective selective Stable Stable of of genome genome Essex Essex USA, USA, by by JP, JP, 1995. 1995. G. G. virus virus Enantiomeric Enantiomeric A, A, study study carbocyclic carbocyclic Phanrı. Phanrı. Abstracts Abstracts in in 17-25, 17-25, B B Acids, Acids, Jl, Jl, 2836-2844, 2836-2844, with with Engle Engle DL). DL). MG, MG, NR, NR, HepG2 HepG2 K. K. DNA, DNA, of of Sci. Sci. and and Acs Acs Quantitative Quantitative 58, 58, Acad. Acad. P, P, chronic chronic chirnpanzees, chirnpanzees, hepatocyte hepatocyte Cheng Cheng 1987. 1987. 62. 62. Bioorg. Bioorg. virus virus Daris Daris in in 47-73, 47-73, JW. JW. differentiated differentiated pilot pilot Arch. Arch. M, M, of of B B Martel Martel novel novel 1986. 1986. in in Bisceglie Bisceglie C, C, a a carbocyclic carbocyclic viral viral Youg Youg transfected transfected 65, 65, produced produced systems, systems, prevention prevention Inhibition Inhibition Acad. Acad. Tyrrell Tyrrell Mullins Mullins A A hepatoblastoma hepatoblastoma Natl. Natl. P, P, Price Price Nudeic Nudeic Production Production patent patent Virol., Virol., hepatitis hepatitis SCH, SCH, duck duck MA. MA. a a anti-hepadnavirus anti-hepadnavirus Virol., Virol., by by virus virus Di Di 1994. 1994. vitro, vitro, Hartman Hartman the the 1987. 1987. JE, JE, D, D, J. J. JL, JL, & & G. G. Activities Activities test test and and Matsubara Matsubara cells cells B B 37-47, 37-47, G. G. the the transfection transfection in in virus virus RH, RH, Ther., Ther., Natl. Natl. 1992. 1992. by by H, H, 4641-4644. 4641-4644. and and with with Proc. Proc. JC, JC, Summers Summers cloned cloned JH. JH. hepatitis hepatitis B B A, A, Bachard Bachard treatment treatment 47, 47, G2 G2 hepatitis hepatitis virus virus Acs Acs for for humarı humarı virus, virus, Gerber Gerber Acs Acs 84, 84, Shvartsman Shvartsman of of Lapointe Lapointe Tovell Tovell primary primary JC, JC, B B after after Cyclopropyl]Methyl Cyclopropyl]Methyl a a the the 331-341, 331-341, R, R, Proc. Proc. B B the the 444-448, 444-448, ST, ST, culture culture virions,]. virions,]. virus virus Cavalcanti Cavalcanti Sundeen Sundeen Purcell Purcell Hep Hep O, O, JS, JS, activity activity of of Cell, Cell, analog analog DNA, DNA, in in AZ, AZ, B B ML, ML, hepatitis hepatitis DE, DE, 49, 49, 1997. 1997. Chemotheraphy, Chemotheraphy, 861-864, 861-864, S, S, 84, 84, far far USA, USA, Treatment Treatment Anti-Viral Anti-Viral Mitsuya Mitsuya line line cell cell in in causes causes BMS-200475, BMS-200475, Pugh Pugh Nucleotides Nucleotides Hepatitis Hepatitis reaction reaction of of Fujiyama Fujiyama Pharmaco/. Pharmaco/. Chao Chao 16, 16, Korenman Korenman MA, MA, metabolism metabolism WA, WA, with with Hoofnagle Hoofnagle Kocy Kocy Sci. Sci. virus virus virus virus JG, JG, state state hepatitis hepatitis JS, JS, T_, T_, cell cell DNA. DNA. H. H. 1987. 1987. Banerjee Banerjee and and hepatitis hepatitis Chen Chen USA, USA, Romet-Lemonne Romet-Lemonne GM. GM. vitro vitro Zelent Zelent Huang Huang replication replication Olgen Olgen B B cells cells B B GS, GS, infectious infectious 2000. 2000. R. R. S, S, of of 127-132, 127-132, infection infection 1991. 1991. chain chain C, C, hepatitis hepatitis Sells Sells Sullivan Sullivan GA, GA, in in drug drug C, C, MW, MW, Sci. Sci. Methods., Methods., TE, TE, particles particles PM, PM, Anti-HBV Anti-HBV 1989. 1989. 7, 7, HBV HBV G2 G2 Acad. Acad. MA, MA, duck duck MA, MA, and and j, j, of of G, G, of of 1998. 1998. hepatitis, hepatitis, Popper Popper of of two two Virol. Virol. (Hydroxymethyl) (Hydroxymethyl) Lett., Lett., Nucleosides, Nucleosides, Bisacchi Bisacchi ra! ra! Slusarchyk Slusarchyk Pierra Pierra jacobs jacobs Broder Broder Synthesis Synthesis dideoxyinosine dideoxyinosine Acad. Acad. Waggoner Waggoner Fried Fried hepatitis hepatitis 2'-deoxyguanosine, 2'-deoxyguanosine, Zahler Zahler Hepatology, Hepatology, 253-268, 253-268, deoxyguanosine deoxyguanosine 8544, 8544, Price Price France, France, 1005-1009, 1005-1009, in in Dusheiko Dusheiko Kitos Kitos son son with with sion sion virus virus Selis Selis cular cular tion tion Acs Acs produce produce duction duction transfected transfected Sells Sells Nat1. Nat1. intermediate intermediate Sureau Sureau integrated integrated Wu Wu merase merase hepatitis hepatitis Tsurimoto Tsurimoto Hep Hep M, M, mental mental hepatoma hepatoma Tuttleman Tuttleman 12. 12. 13. 13. 14. 14. 15. 15. 16. 16. 6. 6. 8. 8. 11. 11. 89-105, 89-105, Status Status 5. 5. 7. 7. 10. 10. 9. 9. 4. 4. ge the the nu and and that, that, vitro vitro 3TC, 3TC, virus, virus, struc Purcell Purcell far far in in chronic chronic B B Current Current as as virus virus R, R, anti-HBV anti-HBV anti-HBV anti-HBV B B proınising proınising of of hepatitis, hepatitis, of CK. CK. effective effective raceınic raceınic far far such such indicates indicates L-fonn L-fonn studied studied only only hepatitis hepatitis 5-fluorocytosine 5-fluorocytosine Chu Chu no no necessary necessary patent patent Girones Girones hepatitis hepatitis K, K, the the The The diazepine-4-one. diazepine-4-one. are are oxaselenolane oxaselenolane and and stili stili CT, CT, treatrnent treatrnent the the 1989. 1989. agents agents be be analogs, analogs, OH OH Lee Lee drugs. drugs. A. A. on on management management evaluated evaluated of of [1.3] [1.3] are are discussion discussion µM) µM) to to the the 1-[2-(hydroxymethyl)-1,3- exhibited exhibited synthesized synthesized BK, BK, ';> ';> H H ıo....;-OH ıo....;-OH N N studies studies Chung Chung the the 1.2 1.2 and and far far HO HO of of 6-amino-8-hydroxy-4H-1-P-D 322-327, 322-327, Dejean Dejean 1 1 based based S, S, 1985. 1985. 50 50 !here !here far far the the antiviral antiviral 9, 9, tlıyminc tlıyminc OH OH hypoxıınthinc hypoxıınthinc anti-HBV anti-HBV ııdrnine ııdrnine guaninr guaninr 5-nuonıcytosinc 5-nuonıcytosinc cyto~ine cyto~ine of of Chun Chun C, C, appear appear (EC nucleoside nucleoside N- N~O N~O H"" H"" /B /B of of Y, Y, faregoing faregoing further further form form organization organization new new Since Since 11). 11). analogues analogues D- 489-495, 489-495, nucleosides nucleosides the the Kaneko, Kaneko, the the of of o~ o~ that that Pourcel Pourcel Choi Choi Structure Structure H,N-{I H,N-{I Among Among synthesized synthesized Se Se 317, 317, Structure Structure P, P, nucleosides nucleosides µM) µM) L-FMAU L-FMAU ~'.J- cytosine cytosine RH, RH, Hepatology, Hepatology, number number . . JH, JH, compounds compounds 11. 11. vivo, vivo, (Figure (Figure a a Compact Compact 52 10. 10. 1.2 1.2 infection. infection. of of and and in in were were HO--. HO--. chemotherapeutics chemotherapeutics other other obvious obvious 50 50 RH. RH. Hong Hong nome, nome, Nature, Nature, Miller Miller Tiollais Tiollais suınınary, suınınary, is is development development 134 134 FTC FTC Figure Figure oxaselenolane oxaselenolane (EC and and 3. 3. among among In In 1. 1. it it 2. 2. HBV HBV Ölgen Ölgen safe safe Conclusion Conclusion References References class class Figure Figure cleosides, cleosides, ture ture activity ribofuranosylimidazo[4,5-e] ribofuranosylimidazo[4,5-e] activity activity The The .. .. a a B B B B L (-) (-) 23, 23, di for for 38, 38, YJ, YJ, (-) ac LS LS ve LS, LS, JA, JA, de BC, BC, 333, 333, ~-L Ber 135 135 mu Nel Chu Chu HM, HM, f\ f\ Schi turn diox An!i 1992. 1992. asym suppl. suppl. the the Cheng Cheng Chem C, C, (-)-L-P P, P, (-l-P-D- L-P-(2S, L-P-(2S, 1993. 1993. infected infected Res., Res., the the Fyfe Fyfe potential potential and and virus virus LW, LW, JL. JL. monax), monax), DR, DR, structure of of of of Xiang Xiang jeong jeong dioxolane dioxolane )eong )eong of of Med., Med., hepa!itis hepa!itis hepatitis hepatitis (-)-P-D-2,6- B B and and as as of of . . 5-fluoro 5-fluoro Antimicrob. Antimicrob. !heir !heir LJ, LJ, YC YC K. K. Tennan! Tennan! f. f. 1995. 1995. CK. CK. unnatural unnatural Mathe Mathe McC!ure McC!ure and and Agents Agents FD, FD, lamivudine lamivudine Frick Frick AJ, AJ, its its lamivudine lamivudine Res.,.11, Res.,.11, CK CK Chemother., Chemother., Schaffer Schaffer of of duck duck 519-528, 519-528, duck duck hepatocyte hepatocyte 6899-6902, 6899-6902, and and Imbach Imbach to to metabolite, metabolite, JP, JP, of of 1996. 1996. site-directed site-directed Antiviral Antiviral M, M, CK, CK, profiles profiles Chu Chu C. C. CK, CK, the the Averette Averette Engl. Engl. of of of of activities activities and and 36, 36, vi!ro, vi!ro, Cheng Cheng Wilson Wilson 33, 33, chronically chronically Chu Chu (Marmota (Marmota its its that that 1996. 1996. metabolite metabolite and and activities activities Alves Alves trial trial Paff Paff LR, LR, in in DL, DL, Z, Z, of of Pharm. Pharm. nucleosides nucleosides Chu Chu Chu Chu 65-70, 65-70, 3008-3011, 3008-3011, Agents Agents JA, JA, A, A, agent, agent, synthesis synthesis its its CN, CN, anti-hepatitis anti-hepatitis New New with with and and K, K, 1994. 1994. Lett., Lett., 13-L-dioxolane-cytidine. 13-L-dioxolane-cytidine. Boudinou! Boudinou! 7, 7, Aldrich Aldrich Antimicrob. Antimicrob. through through DC, DC, resistance resistance 55, 55, virus virus anabolic anabolic Gao Gao FD, FD, FD, FD, Pharmacokinetics Pharmacokinetics J, J, and and clearance clearance (-)-P-D-2,6-diaminopurine (-)-P-D-2,6-diaminopurine anti-HBV anti-HBV of of The The Kim Kim Evidence Evidence Somrnadossi Somrnadossi Generation Generation Sharunugana!han Sharunugana!han Cannon Cannon 1957-1960, 1957-1960, Chang Chang HM, HM, Med.Chem., Med.Chem., of of therapy therapy SH, SH, Res., Res., RF. RF. cis-5-fluoro-1-[2-(hydroxymethyl) cis-5-fluoro-1-[2-(hydroxymethyl) and and Wurster Wurster Liot!a Liot!a antiviral antiviral Condreay Condreay and and W. W. f. f. woodchucks woodchucks S, S, AM, AM, RF, RF, rnonkeys, rnonkeys, 1992. 1992. preliminary preliminary GR. GR. 40, 40, rapid rapid infection, infection, of of RF, RF, RF, RF, analogue analogue dioxolane dioxolane 8321-8330, 8321-8330, mutants mutants Liu Liu M, M, DL). DL). Antimicrob. Antimicrob. asymmetric asymmetric Pharmacokine!ics Pharmacokine!ics in in (+)-L-P-dioxolane-T (+)-L-P-dioxolane-T RE, RE, B B A A Saputelli Saputelli activity activity Boudinot Boudinot Tetrahedron Tetrahedron 4R)-Dioxolanyl 4R)-Dioxolanyl WI-l, WI-l, for for Boudino! Boudino! Chemother., Chemother., X, X, 68, 68, demonstrate demonstrate ), ), dioxolane dioxolane Cancer Cancer 2',3'-dideoxycytidine 2',3'-dideoxycytidine M. M. Mason Mason antiviral antiviral McClure McClure rhesus rhesus Schinazi Schinazi P, P, PF, PF, and and Painter Painter potential potential Davis Davis an!i-HIV an!i-HIV of of Schinazi Schinazi RF. RF. Aubertin Aubertin vitre, vitre, Sharunuganaıhan Sharunuganaıhan Guo Guo Tyrrell Tyrrell Nampalli Nampalli a a in in 1995. 1995. 1994. 1994. Schinazi Schinazi Schinazi Schinazi 2686-2692, 2686-2692, 1994. 1994. Miller Miller agents: agents: Chem. Chem. Virol., Virol., which which Development Development RF, RF, G, G, BH, BH, L-~-(2S, L-~-(2S, Cullen Cullen in in PA, PA, Dornsife Dornsife and and as as hepa!i!is hepa!i!is cytotoxicities, cytotoxicities, irnmunodeficiency irnmunodeficiency relationships, relationships, Chemolher., Chemolher., Rubin Rubin enantiomers enantiomers required required f. f. nucleoside nucleoside KP, KP, 36, 36, KL, KL, synthesis, synthesis, 81, 81, PughJ, PughJ, MC, MC, JW, JW, guanosine, guanosine, JW, JW, JV, JV, polymerase polymerase during during HO, HO, HO, HO, Polen! Polen! is is Anticancer Anticancer CK CK C, C, RF RF 1994. 1994. DJ, DJ, and and (+) (+) D, D, P-L-2',3'-dideoxy-3'-!hiacytidine P-L-2',3'-dideoxy-3'-!hiacytidine 1657-1661, 1657-1661, virus virus oxolane oxolane Schinazi Schinazi Fisher Fisher Agents Agents chronic chronic 2,6-diaminopurine 2,6-diaminopurine Baldwin Baldwin olane olane other., other., cary cary Rajagopalan Rajagopalan diaminopuriiı.e diaminopuriiı.e 1292-1297, 1292-1297, Antiviral Antiviral 381, 381, guanosine guanosine Furman Furman Rajagopalan Rajagopalan Beach Beach dioxolane-C dioxolane-C Kim Kim son son CK. CK. tagenesis tagenesis rivative rivative ~ctt ~ctt enantiomer enantiomer suppL suppL human human ducks, ducks, Chu Chu gogne gogne 4S)- activi!y activi!y over over Beach Beach Gosselin Gosselin Kim Kim anti-HIV anti-HIV Schinazi Schinazi tivities, tivities, configuration, configuration, -l,3-oxa!hiolan-5-yl]cytosine, -l,3-oxa!hiolan-5-yl]cytosine, and and novel novel nazi nazi Grove Grove Tuttle Tuttle virus virus Fourel], Fourel], YC. YC. metric metric 37. 37. 39. 39. 30. 30. 38. 38. 31. 31. 33. 33. 3;ı 3;ı 36. 36. 35. 35. 34. 34. l B, B, B, B, of of C. C. A, A, vi la 16, 16, ac Ef Vi- Lo nu Fox Fox An 336- ura 2',3' Syn Res., Res., anti com duck duck HIV Med. Med. virus virus of of virus virus Anti in in 1992. 1992. 1979. 1979. 26-29, 26-29, 91-94, 91-94, Virol., Virol., Treaı serum serum M, M, C. C. purine purine N, N, 33, 33, of of and and in in ]. ]. A, A, for for virus virus Trepo Trepo in in 123. 123. L. L. of of and and Biological Biological Med., Med., C C DL. DL. Chomel Chomel 27, 27, arabinosyl 1-{2-deoxy- fluoro-P-D E. E. June June 127 127 Savarese Savarese 21-24, 21-24, inhibit inhibit Maısuda Maısuda Med. Med. acyclovir, acyclovir, International International Trepo Trepo C, C, Efficacy Efficacy virus virus Antiviral Antiviral level level assay assay and and to to suppression suppression J J hepatitis hepatitis hepatitis hepatitis 16, 16, 1990. 1990. of of 22, 22, jewell jewell 1995. 1995. replication, replication, SE, SE, JJ, JJ, B B CK, CK, Lopez Lopez F. F. 6th 6th lamivudine, lamivudine, Clerq Clerq Tyrrell Tyrrell abilities abilities Invest. Invest. Synthesis Synthesis arabinofuranosyl Greenberg Greenberg Chem., Chem., L-arabinofuranosyl L-arabinofuranosyl W, W, antiherpes antiherpes K, K, cytosines cytosines 2'-fluoro 2'-fluoro Chemother., Chemother., woodchucks, woodchucks, DNA DNA Bartholomew Bartholomew rapid rapid Fox Fox De De 2001 2001 jacquet jacquet U, U, Sciences, Sciences, MJ, MJ, ducks, ducks, Chu Chu virus virus culture culture a a with with Nucleosides. Nucleosides. of of 129. 129. Chem., Chem., lan lan C, C, Clin. Clin. and and 473-475, 473-475, T, T, relationships, relationships, Straus Straus B B and and the the ER, ER, in in 396-397, 396-397, Synıhesis Synıhesis 5-substituted 5-substituted Med. Med. KA, KA, Jj. Jj. RS, RS, virus virus K, K, cell cell hepatitis hepatitis Hiroıa Hiroıa 34, 34, of of woodchuck woodchuck f. f. Agents Agents woodchuck woodchuck Hepatology, Hepatology, B B arabinosyl-pyrimidine arabinosyl-pyrimidine ...... A A Med. Med. ducks ducks infected infected 345, 345, Robins Robins AM, AM, of of !riphosphaıes !riphosphaıes CK CK effects effects U, U, Ooka Ooka Fox Fox Derivatives, Derivatives, infected infected 129-136. 129-136. f. f. Schiff Schiff on on sera, sera, jacque! jacque! S, S, Lunel-Fabiani Lunel-Fabiani 1991. 1991. JH. JH. results results G. G. Klein Klein Reichman Reichman and and hepatitis hepatitis Savani Savani and and the the in in Synthesis Synthesis E, E, O, O, HS, HS, and and 26. 26. Chu Chu RP, RP, 1983. 1983. 5-alkenyl-1-(2-deoxy-2- K, K, Nucleosides. Nucleosides. TL, TL, TL, TL, Wa!anabe Wa!anabe uracils, uracils, C C by by hepatitis hepatitis Lancet, Lancet, ı1ucleosides, ı1ucleosides, 2'-fluoro-2'-deoxy- Pharmaceutical Pharmaceutical 110. 110. 2000. 2000. Suzuki Suzuki 2',3'-dideoxynucleosides 2',3'-dideoxynucleosides Bisceglie Bisceglie JJ JJ and and comparison comparison O, O, Sci.. Sci.. Chemother Chemother Su Su Su Su lnhibitory lnhibitory Reichman Reichman 217-228, 217-228, inhibit inhibit Antimicrob. Antimicrob. Milman Milman DNA DNA replication replication chronically chronically Dohin Dohin humarı humarı Imidazole Imidazole Hantz Hantz 1993. 1993. T T on on chronically chronically structure-activity structure-activity Hoofnagle Hoofnagle duck duck Perrillo Perrillo 2'deoxy-2'fluoro-D 2'deoxy-2'fluoro-D C. C. Di Di Fisher Fisher nucleosides nucleosides 1992. 1992. J, J, Lopez Lopez 15, 15, Fox Fox nucleosides, nucleosides, 152-156, 152-156, Y, Y, WX, WX, in in 2'-fluorinated 2'-fluorinated of of vivo vivo 1984, 1984, KA, KA, KA, KA, on on KA, KA, sorne sorne and and of of of of Allaudeen Allaudeen Ma Ma on on JL, JL, Li Li B77, B77, and and Hanız Hanız antiviral antiviral Turkey, Turkey, patients, patients, chimpanzees chimpanzees which which in in Agenls Agenls MP, MP, 26, 26, ?harın. ?harın. DLJ, DLJ, !, !, !, !, 4, 4, and and S, S, of of BE BE of of O, O, Luo Luo Res., Res., MW, MW, of of polymerase polymerase MW, MW, Trepo Trepo nucleosides, nucleosides, of of some some J. J. liver liver 1989. 1989. pyrimidine pyrimidine E-5-(2-bromovinyl)-2'-deoxyuridine, E-5-(2-bromovinyl)-2'-deoxyuridine, C C B. B. J, J, and and Nucleosides. Nucleosides. 122-126, 122-126, 187-199, 187-199, liviral liviral Chem., Chem., Walanabe Walanabe Symposium Symposium 2-halogeno-~-D-arabinofuranosyl) 2-halogeno-~-D-arabinofuranosyl) 339, 339, hepadnavirus, hepadnavirus, tro tro Lee Lee and and pounds pounds Korba Korba Hanız Hanız and and JJ. JJ. (2'-deoxy-2'-fluoro-iJ-D-arabinofuranosyl)-5-iodocytosine (2'-deoxy-2'-fluoro-iJ-D-arabinofuranosyl)-5-iodocytosine Fox Fox Fourel Fourel hepadnaviral hepadnaviral infected infected 1984. 1984. Benhamou Ankara, Ankara, dideoxy-3'-thiacytidine dideoxy-3'-thiacytidine thesis thesis mivudine mivudine cils, cils, Beames Beames ment ment SuppL SuppL Tyrrell Tyrrell Fried Fried Wa!anabe Wa!anabe Activities Activities Chun Chun pez pez Triazole Triazole viral viral 4, 4, 37, 37, pyrimidine pyrimidine arabinofuranosyl) arabinofuranosyl) Olgen Olgen Fourel Fourel Wa!anabe Wa!anabe and and cleosides cleosides fects fects microb. microb. DNA DNA tivity tivity Diensıag Diensıag Inhibition Inhibition pyrimidine pyrimidine replication replication ABAD ABAD F F 17. 17. 18. 18. 19. 19. 26. 26. 22. 22. 28. 28. 25. 25. 27. 27. 23. 23. 20. 20. 29. 29. 24. 24. 21. 21. 1 1 G, G, L 2' in 30, 30, K.; K.; and and Dis con syn anti l-(2- nov CK. CK. j. j. Med. Med. Drug Drug Phar [4,5-E] [4,5-E] of of YC. YC. Phase Phase J J Res., Res., novel novel ofa ofa and and FD. FD. Chu Chu (HBV) (HBV) short short and and FD. FD. 1350-1353, 1350-1353, (L-FMAU) (L-FMAU) a a replication replication model model neurologic neurologic H. H. Levy, Levy, Gumina Gumina ), ), Nucleotides Nucleotides !. !. ), ), (9), (9), N.; N.; Cheng Cheng studies studies analogue analogue Du Du imidazo imidazo virus virus virus virus activity activity Du Du 12 12 S, S, B B Anh"viral Anh"viral severe severe M. M. C., C., B B efficient, efficient, Synthesis Synthesis Boudinot Boudinot 195-201. 195-201. C, C, Boudinot Boudinot 1997. 1997. nucleosides, nucleosides, 1999. 1999. Biopharm. Biopharm. by by 7, 7, viral viral Krakoff, Krakoff, An An Peek Peek Res., Res., B B RF, RF, 36, 36, vivo, vivo, and and Trepo Trepo 1996. 1996. Raber, Raber, S.; S.; and and Nucleosides Nucleosides aromatic, aromatic, RS. RS. in in hepatitis hepatitis Pierra Pierra 1989, 1989, nucleoside nucleoside LA, LA, rats, rats, C, C, S. S. pharmacokinetic pharmacokinetic hepatitis hepatitis S.; S.; A52, A52, CK CK 331-335, 331-335, of of 2000. 2000. L, L, CK CK in in Pharm. Pharm. and and 34, 34, terminated terminated Schinazi Schinazi (3), (3), 94&-957, 94&-957, Borel Borel pharmacodynamic pharmacodynamic planar, planar, Ma Ma system, system, Drugs Drugs Chu Chu Chu Chu Legha, Legha, l-(2-fluoro-13-L-arabinofuranosyl)-5- purine purine S, S, 18 18 oxaselenolane oxaselenolane inhibits inhibits Graham Graham Hosmane Hosmane rats, rats, model model Schmidt, Schmidt, Res., Res., S, S, YC, YC, anti-hepatitis anti-hepatitis T, T, ), ), and and T, T, R, R, absorbtion absorbtion ring ring in in of of of of M.; M.; l-(2-deoxy-2-fluoro-13-L-arabinofuranosyl) l-(2-deoxy-2-fluoro-13-L-arabinofuranosyl) New New (1-11), (1-11), 3906-3912, 3906-3912, L.; L.; (L-FMAU) (L-FMAU) (FMAU) (FMAU) j. j. of of Ma Ma Adds, Adds, A. A. 17 17 Ma Ma oral oral hepatocytes hepatocytes jacob jacob analog, analog, Sood Sood Olgen Olgen potent potent l-(2-deoxy-2-fluoro-13-D-arabinofuranosyl)-5- 5:7-fused, 5:7-fused, Aguesse Aguesse Cheng Cheng (21), (21), B, B, JD, JD, a a Antiviral Antiviral Invest. Invest. JD, JD, F, F, E, E, 43 43 woodchuck woodchuck and and of of activities activities HNI, HNI, CK, CK, diazepine diazepine 1996. 1996. Nucleic Nucleic ring-expanded ring-expanded the the primary primary Chem. Chem. [1,3] [1,3] Chu Chu and and viral viral Gullen Gullen taining taining Disposition, Disposition, thesis thesis el el Chen Chen methyluracil methyluracil Wright Wright continuous continuous Wright Wright bioavailability bioavailability fection, fection, 1995. 1995. in in Pharmacokinetic Pharmacokinetic fluoro-5-methyl-13-L-arabinofuranosyl)uracil fluoro-5-methyl-13-L-arabinofuranosyl)uracil A24, A24, macokinetics macokinetics -5-methyluracil -5-methyluracil Abbruzzese, Abbruzzese, nucleoside nucleoside Fluoro-5-methyl-Jj-L-arabinofuranosyluracil, Fluoro-5-methyl-Jj-L-arabinofuranosyluracil, Zoulim Zoulim in in toxicity. toxicity. trial trial methyluracil methyluracil Tennant Tennant Castellanos, Castellanos, 52. 52. 51. 51. 50. 50. 49. 49. 47. 47. 48. 48. 46. 46. of of of of (j3- (L Liu Liu and and 798- l-(2- nov MA, MA, 2',3' hep Xiang Xiang {HIV) {HIV) a a Use Use Cheng Cheng of of Chem., Chem., human human human human Agents Agents reverse reverse in in TS, TS, Chemo 979-981, 979-981, 37, 37, Dutsch of of antiviral antiviral as as Inhibition Inhibition of of of of CG, CG, E, E, 2'-fluoro-5- YC. YC. and and Lin Lin Antimicrob. Antimicrob. synthesis synthesis virus virus Epstein-Barr Epstein-Barr uracil uracil Med. Med. 39, 39, Ascenzi Ascenzi virus virus (~-L-d4C) (~-L-d4C) YC. YC. ]. ]. O, O, GE GE Agents Agents B B Chem., Chem., and and Wang Wang and and synthesis synthesis 1996. 1996. potential potential BH, BH, Gullen Gullen Cheng Cheng K, K, 2',3'-Dideoxy-~-L-5- Antimicrob. Antimicrob. inhibitors inhibitors inhibitors inhibitors evaluation evaluation as as vitro, vitro, Cheng Cheng JP, JP, Hanız Hanız Med. Med. virus virus YL, YL, uridine, uridine, DNA DNA in in Design Design L-nucleoside, L-nucleoside, B B ]. ]. C, C, Pharmacokinetics Pharmacokinetics vivo. vivo. hepatitis hepatitis CK, CK, 380-386, 380-386, Chemother., Chemother., potent potent Baldwin Baldwin potent potent Zhu Zhu YC. YC. in in viral viral Antimicrob. Antimicrob. CK. CK. Dutschuman Dutschuman 40, 40, (HIV) (HIV) CK. CK. Chu Chu novel novel Borel Borel and and duck duck FD, FD, immunodeficiency immunodeficiency biological biological 1996. 1996. a a nucleosides nucleosides and and MC, MC, SB, SB, (HBV), (HBV), E, E, Chu Chu hepatitis hepatitis YL, YL, Agents Agents Sommadossi Sommadossi Chu Chu by by virus virus Pai Pai Cheng, Cheng, Liu Liu and and Shanmuganathan Shanmuganathan far far suppress suppress vitro vitro (HBV) (HBV) YC, YC, JF, JF, virus virus Zhu Zhu GQ, GQ, human human inhibits inhibits 448-453, 448-453, in in 1996. 1996. exceptionally exceptionally B B virus virus C, C, Boudinot Boudinot and and TW, TW, MZ, MZ, MZ, MZ, Du Du Chemother., Chemother., B B SH, SH, agent agent woodchucks, woodchucks, 40, 40, virus virus Yao Yao Dannaoui Dannaoui Cheng Cheng two two Ma Ma both both B B BC, BC, JW, JW, in in Luo Luo Luo Luo F, F, and and Liu Liu against against SB, SB, Antimicrob. Antimicrob. Synthesis Synthesis Trepo Trepo 1997. 1997. GE, GE, CK, CK, hepatitis hepatitis 1994. 1994. TS, TS, TS, TS, SB, SB, Pai Pai 1757-1759, 1757-1759, 2',3'-dideoxy-2',3'-didehydro-j3-L-5-fluorocytidine 2',3'-dideoxy-2',3'-didehydro-j3-L-5-fluorocytidine hepatitis hepatitis antiviral antiviral Pai Pai Agents Agents 1995. 1995. of of ther., ther., virus, virus, 2'-fluoro-5-methyl-~-L-arabinofuranosyluracil 2'-fluoro-5-methyl-~-L-arabinofuranosyluracil el el methyl-~-L-arabinofuranosyl methyl-~-L-arabinofuranosyl Chu Chu FMAU) FMAU) fluoro-5-methyl-13-L-arabinofuranosyl) fluoro-5-methyl-13-L-arabinofuranosyl) Witcher Witcher Tennant Tennant YJ, YJ, 39, 39, Chemther., Chemther., of of 2',3'-dideoxy-2',3'-didehydro-13-L-cytidine 2',3'-dideoxy-2',3'-didehydro-13-L-cytidine Lin Lin hepatitis hepatitis immunodeficiency immunodeficiency L-Fd4C), L-Fd4C), Lin Lin fluorocytidine fluorocytidine Zoulim Zoulim man man SH, SH, and and 803, 803, agents agents YC. YC. transcription transcription dideoxy-L-pyrimidine dideoxy-L-pyrimidine atocytes, atocytes, 136 136 45. 45. 44. 44. 43. 43. Ölgen Ölgen 42. 42. 40. 40. 41. 41.