Asymmetric synthesis and biological evaluation of .beta.-L-(2R,5S)- and .alpha.-L-(2R,5R)-1,3-oxathiolane-pyrimidine and -purine nucleosides as potential anti-HIV agents

239

133

A novel anti-hepatitis B virus (anti-HBV) agent, 2-fluoro-5-methyl-␤-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.A number of nucleosides have been reported to be antihepatitis B virus (anti-HBV) agents, although none of them have yet been proven to be clinically useful. As a part of our antiviral drug discovery program for HBV, we recently have reported the syntheses and anti-HBV activities of dioxolane (14, 15) and oxathiolane (1,8,13) nucleosides. (Ϫ)-␤-L-Dioxolane-cytosine has been found to be the most potent anti-HBV agent (50% effective concentration ϭ 0.0005 M in 2.2.15 cells), although the compound was the most toxic (50% inhibitory concentration ϭ 0.26 M in CEM cells) among those tested (15). Among the oxathiolane cytosine nucleosides we evaluated, (Ϫ)-␤-L-oxathiolane-cytosine has the most potent anti-HBV activity (50% effective concentration ϭ 0.01 M) and a favorable cytotoxicity (Ͼ50 M in CEM cells) (1). Interestingly, the (Ϫ)-␤-L isomer of this compound resisted deoxycytidine deaminase, while the (ϩ)-␤-D isomer was deaminated under similar conditions (3).Recently, an increasing number of L nucleosides have been reported to be antiherpesvirus (23), anti-human immunodeficiency virus (anti-HIV) (2,6,13,14,16,19), and anti-HBV (1,7,8,10,11,15,16) agents. Furthermore, some of the L nucleosides have been found to be more potent than the corresponding D nucleosides (6,13,14). Previously, 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyluracil (FMAU) and 2Ј-fluoro-5-ethyl-␤-Darabinofuranosyluracil (FEAU) were reported (5, 24, 27) to be extremely potent antiviral agents against herpesvirus and HBV, respectively. However, the myelosuppression and neurotoxicity of FMAU limit its usefulness as a clinically effective antiviral agent. In view of the discovery that several nucleosides with the unnatural L configuration are selective antiviral agents, it was of interest to synthesize several 2Ј-fluoro-substituted (arabino configuration) nucleosides with the L configuration as potential antiviral agents, anticipating that these nucleosides will give lower toxicities than the corresponding D isomers. Thus, we report here the preliminary syntheses and antiviral activities of several pyrimidine nucleosides for which the corresponding D isomers have been known to exhibit potent antiviral activities.Synthesis. 1-O-Acetyl-2,3,5-tri-O-benzoyl-␤-L-ribofuranose (compound 1) was prepared from L-ribose (Fig. 1). The fully protected L-ribose compound 1 was selectively debenzoylated at the C-2 position and then was converted to the 2-fluorinated sugar (compound 3) according to the method described for the corresponding D isomer (25). The 2-fluorosugar (arabino configuration) compound 3 was c...

Section: A Novel Anti-hepatitis B Virus (Anti-hbv) Agent 2-fluoro-5-mentioning

confidence: 99%

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confidence: 99%

Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus

Chu

Shanmuganathan

et al. 1995

239

133

“…Thus, on the one hand, synthetic ,B-L-thymidine has been shown to be selectively phosphorylated by herpes simplex virus type 1 thymidine kinase and to markedly reduce herpes simplex type 1 replication in HeLa cells (41). Although initially reported as having no antiviral activity (24), P-L-2',3'-dideoxycytidine, the mirror image of 2',3'-dideoxycytidine (DDC; or zalcitabine or Hivid), was shown by Mansuri et al (22) (2,5,16,34) enantiomers exhibited more potent anti-HIV activities than the corresponding racemates or D isomers provides a strong rationale for studying the mirror images of other previously described D enantiomers. Among them are L-DDC and 13-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), since studies of the structure-activity relationship of pyrimidine nucleosides modified at the 5 position indicated that their potencies can be preserved or increased by having this position modified with a halogen.…”

mentioning

confidence: 99%

“…For instance, when the 5 position of DDC was substituted with a fluorine atom, both anti-HIV activity and potency were retained (17,38). On the other hand, in the 2-hydroxymethyl-1,3-dioxolanyl (18) and -oxathiolanyl (16,36) series, the P-L-5-fluorocytosine derivatives ( Fig. 1; X and Y = F) were found to be the most potent anti-HIV compounds among those tested, although the dioxolanyl analog also demonstrated some toxicity.…”

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confidence: 99%

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Gosselin

Schinazi

Sommadossi

et al. 1994

131

The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.

“…Since the discovery of 3TC, however, a number of nucleosides with the unnatural L configuration have emerged as potent antiviral agents. Both 3TC and FTC [(Ϫ)-␤-L-2Ј,3Ј-dideoxy-5-fluoro-3Ј-thiacytidine] show potent antiviral activity against HIV and hepatitis B virus, with favorable pharmacokinetic and toxicity profiles (20,43). Therefore, structural features and conformational preferences of the D and L enantiomers, as well as their interactions with the target enzymes, have been the critical issue to be studied (4,26,27,39,40,43).…”

mentioning

confidence: 99%

Molecular Modeling Approach to Understanding the Mode of Action ofl-Nucleosides as Antiviral Agents

Lee

Chu

2001

Self Cite

Antiretroviral therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection has proven effective in extending the life and enhancing the quality of life of patients with AIDS (25). Thus far, six nucleoside reverse transcriptase (RT) inhibitors (NRTIs), four protease inhibitors, and three non-NRTIs have been approved by the Food and Drug Administration. In particular, NRTIs continue to be the mainstay of antiretroviral therapy (24, 31). For example, triple-combination therapy, consisting of zidovudine (AZT) (3Ј-azido-3Ј-deoxythymidine) (9,17,18,21,28) , 33, 34), and a protease inhibitor, is being used as the primary regimen for AIDS treatment (11,15). Therefore, a complete understanding of the mechanism of action of NRTIs at the molecular level continues to be an important scientific objective for design and development of more effective and less toxic agents.The NRTIs bear structural features common to 2Ј,3Ј-dideoxynucleosides, and the majority of the approved drugs have the natural D configurations: AZT, ddC (2Ј,3Ј-dideoxycytidine) (1, 5, 46), ddI (2Ј,3Ј-dideoxyinosine) (8, 12, 29, 47), d4T (2Ј,3Ј-didehydro-2Ј,3Ј-dideoxythymidine) (16,22), and abacavir (1592U89; succinate) (10, 38). Since the discovery of 3TC, however, a number of nucleosides with the unnatural L configuration have emerged as potent antiviral agents. Both 3TC and FTC [(Ϫ)-␤-L-2Ј,3Ј-dideoxy-5-fluoro-3Ј-thiacytidine] show potent antiviral activity against HIV and hepatitis B virus, with favorable pharmacokinetic and toxicity profiles (20,43). Therefore, structural features and conformational preferences of the D and L enantiomers, as well as their interactions with the target enzymes, have been the critical issue to be studied (4,26,27,39,40,43).The activation of nucleoside RT inhibitors involves two major events: phosphorylation by kinases and the interaction of the deoxynucleoside triphosphate (dNTP) with the RT (14,30,35). The antiviral activity of 2Ј,3Ј-dideoxynucleosides is dependent on their phosphorylation by cellular kinases in the cytoplasm to the corresponding 5Ј-triphosphates. These triphosphates compete with the corresponding endogenous nucleoside triphosphates at the catalytic site of the HIV-1 RT, and also, upon incorporation into the nascent DNA strand the nucleotides act as chain terminators of the DNA elongation. The initial phosphorylation of nucleosides requires several cellular kinases, such as thymidine kinase, deoxycytidine kinase, and adenosine kinase, and the activities of these kinases depend on the nature of the heterocyclic base as well as the structure and stereochemistry of the carbohydrate moiety (36).However, as three-dimensional structures of these kinases have not yet been determined, it is difficult to envision how the initial phosphorylation is carried out for unnatural nucleosides, such as L-nucleosides, without compromising the stereochemical requirements of the enzymes and/or the nucleosides. Furthermore, the active conformation of the 5Ј-triphosphates at the site of the RT is not well u...