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ABSTRACT: The synthesis of new ribo and 2'-β-C-methyl ribo Janus type nucleosides J-AA, J-AG and J-AU is reported along with their ability to block HCV and HIV replication. Their toxicity was also assessed in Huh7, human lymphocytes, CEM and Vero cells.
Bioorganic & medicinal chemistry letters 03/2013; · 2.65 Impact Factor
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Franck Amblard,
Hongwang Zhang,
Longhu Zhou,
Junxing Shi,
Drew R Bobeck,
James H Nettles,
Satish Chavre,
Tamara R McBrayer,
Philip Tharnish,
Tony Whitaker,
Steven J Coats,
Raymond F Schinazi
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ABSTRACT: Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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ABSTRACT: An efficient synthetic route to biologically relevant (-)-5-fluorocarbodine 6 has been developed. Direct coupling of N6 protected 5-fluorocytosine 15 with cyclopentenyl intermediate 13, followed by formation, via ring closing metathesis, of a macrocycle between the base and the carbocyclic sugar moiety, allowed for a facial selective hydrogenation of the sugar double bond to give, exclusively, the desired 4'-beta stereoisomer.
The Journal of Organic Chemistry 12/2012; · 4.45 Impact Factor
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ABSTRACT: A new and facile synthetic pathway to metabolically stable 5'-methylene-bis(pivaloyloxymethyl)(POM)phosphonate furanonucleoside prodrugs is reported. The key step involves a Horner-Wadsworth-Emmons reaction of a tetra(pivaloyloxymethyl) bisphosphonate salt with appropriately protected 5'-aldehydic nucleosides. This efficient approach was applied for the synthesis HCV related 2'-deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides.
Organic Letters 08/2012; 14(17):4426-9. · 5.86 Impact Factor
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Hongwang Zhang,
Longhu Zhou, Franck Amblard,
Junxing Shi,
Drew R Bobeck,
Sijia Tao,
Tamara R McBrayer,
Phillip M Tharnish,
Tony Whitaker,
Steven J Coats,
Raymond F Schinazi
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ABSTRACT: Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented.
Bioorganic & medicinal chemistry letters 05/2012; 22(14):4864-8. · 2.65 Impact Factor
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Junxing Shi,
Longhu Zhou, Franck Amblard,
Drew R Bobeck,
Hongwang Zhang,
Peng Liu,
Lavanya Bondada,
Tamara R McBrayer,
Phillip M Tharnish,
Tony Whitaker,
Steven J Coats,
Raymond F Schinazi
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ABSTRACT: NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.
Bioorganic & medicinal chemistry letters 03/2012; 22(10):3488-91. · 2.65 Impact Factor
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ABSTRACT: An efficient method for the synthesis of nucleoside phosphoramidates prodrugs (6a-f) has been developed that employs a simple protection/deprotection sequence of the nucleoside with benzyloxycarbonyl (Cbz). The coupling reaction of Cbz-protected derivatives (5a-f) with phenyl-(ethoxy-L-alaninyl)-phosphorochloridate (7), followed by Cbz group removal by hydrogenolysis provided the phenyl phosphoramidate ProTides (6a-f) in excellent overall yields.
Tetrahedron 07/2011; 67(30):5487-5493. · 3.03 Impact Factor
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Hong-Wang Zhang,
Steven J Coats,
Lavanya Bondada, Franck Amblard,
Mervi Detorio,
Ghazia Asif,
Emilie Fromentin,
Sarah Solomon,
Aleksandr Obikhod,
Tony Whitaker,
Nicolas Sluis-Cremer,
John W Mellors,
Raymond F Schinazi
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ABSTRACT: Based on the promising drug resistance profile and potent anti-HIV activity of beta-d-3'-azido-2',3'-dideoxyguanosine, a series of purine modified nucleosides were synthesized by a chemical transglycosylation reaction and evaluated for their antiviral activity, cytotoxicity, and intracellular metabolism. Among the synthesized compounds, several show potent and selective anti-HIV activity in primary lymphocytes.
Bioorganic & medicinal chemistry letters 11/2009; 20(1):60-4. · 2.65 Impact Factor
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Chemical Reviews 10/2009; 109(9):4207-20. · 40.20 Impact Factor
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Nicolas Sluis-Cremer,
Dianna Koontz,
Leda Bassit,
Brenda I Hernandez-Santiago,
Mervi Detorio,
Kim L Rapp, Franck Amblard,
Lavanya Bondada,
Jason Grier,
Steven J Coats,
Raymond F Schinazi,
John W Mellors
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ABSTRACT: Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3'-azido-2',3'-dideoxypurine nucleosides (ADPNs) 3'-azido-2',3'-dideoxyadenosine (3'-azido-ddA) and 3'-azido-2',3'-dideoxyguanosine (3'-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC50s] range from 0.19 to 2.1 microM for 3'-azido-ddG and from 0.36 to 10 microM for 3'-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3'-azido-ddA and 3'-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC50 change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC50 change of <3.5-fold). In addition, 3'-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3'-azido-ddG is efficiently phosphorylated to 3'-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.
Antimicrobial Agents and Chemotherapy 07/2009; 53(9):3715-9. · 4.84 Impact Factor
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ABSTRACT: A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-alpha-(hydroxymethyl)cyclopent-2-ene-1-alpha-yl]guanine (CBV) 5, (-)-beta-D-(2R,4R)-1,3-dioxolane-guanosine (DXG) 6, 3'-azido-3'-deoxy-guanosine (AZG) 7, and 2'-C-methylguanosine 8. Their in vitro activity against HIV and HCV was evaluated and correlated to their ability to degrade to their purine counterpart.
European journal of medicinal chemistry 05/2009; 44(10):3845-51. · 3.27 Impact Factor
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ABSTRACT: A series of new bisphenol derivatives bearing allylic moieties were synthesized as potential analogs of honokiol and/or magnolol. Certain compounds exhibited specific anti-proliferation activity against SVR cells and moderate anti-HIV-1 activity in primary human lymphocytes. Compound 5h was the most potent compound and its anti-tumor activity was evaluated in vivo.
Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4428-31. · 2.55 Impact Factor
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ABSTRACT: Honokiol (HNK), a naturally occurring biphenyl, possesses potent antineoplastic and antiangiogenic properties. We investigated the in vitro and in vivo activity of HNK against breast cancer. HNK exhibited potent anti-proliferative activity against breast cancer cell lines and enhanced the activity of other drugs used for the treatment of breast cancer. In vivo, HNK was highly effective against breast cancer in nude mice. We identified two different effects of HNK on breast cancer cells: cell cycle inhibition, observed at lower doses of HNK, and induction of apoptosis, observed at higher doses of the compound. Our data suggest that HNK is a systemically available, non-toxic inhibitor of breast cancer growth and should be examined for clinical applications.
International Journal of Oncology 07/2007; 30(6):1529-37. · 2.40 Impact Factor
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ABSTRACT: A separation of honokiol 1 from the closely structurally related magnolol 2 was developed. Honokiol demonstrated weak activity against HIV-1 in human lymphocytes.
Journal of Medicinal Chemistry 07/2006; 49(11):3426-7. · 5.25 Impact Factor
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ABSTRACT: The synthesis of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d]pyrimidine series is described. These compounds were evaluated against HIV and HSV in order to determine their spectrum of antiviral activity. Their cytotoxicities against PBM, CEM and VERO cells were also determined. Compounds 21d and 24b displayed moderate EC50s of 2.7 and 4.9 microM, respectively, against HIV-1 and of 6.3 and 4.8 microM, respectively, against HSV. Nevertheless, these compounds also showed cellular toxicity, suggesting that the antiviral effects are secondary to the toxic effects.
Bioorganic & Medicinal Chemistry 03/2005; 13(4):1239-48. · 2.92 Impact Factor
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ABSTRACT: The enantiomeric synthesis of L-cyclopentenyl nucleosides is described. The key intermediate (+)-cyclopentenyl alc. (I) was prepd. from methyl-α-D-galactopyranoside using a ring closing metathesis reaction. Transformation of the allylic alc., I, into the allylic acetate or carbonate, allows their coupling with purine and pyrimidine bases under Pd(0)-catalyzed Tsuji-Trost allylic alkylation's to yield the carbocyclic nucleosides. The Pd catalyzed reaction was found to require the use of AlEt3.
Tetrahedron 01/2004; 60(38):8397. · 3.03 Impact Factor
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Tetrahedron. 61(3):537-544.
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ABSTRACT: In this paper, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleoside analogues of the anti-HIV AZT, and FLT drugs. The key step of those syntheses is a Pd(0) cross-coupling at C5 position under Sonogashira conditions. Finally, based on their in vitro anti-HIV activities and their cytotoxicity on PBM, CEM, and VERO cell lines, the best compounds were the 2′,3′-dideoxy-3′-fluoro-5-(bromo-2-iodo)vinyluridine (10b, EC50 of 0.6 μM), and the 3′-azido-2′,3′-dideoxy-5-(bromo-2-iodo)vinyluridine (16b, EC50 of 1.1 μM).Graphical abstract
Tetrahedron. 64(19):4444-4452.
