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1.
Molecules ; 25(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32486052

RESUMO

We report studies on radical-initiated fragmentations of model 1,5-dideoxyhomoribofuranose derivatives with bromo, chloro, and tosyloxy substituents on C2. The effects of stereochemical inversion at C2 were probed with the corresponding arabino epimers. In all cases, the elimination of bromide, chloride, and tosylate anions occurred when the 3-hydroxyl group was unprotected. The isolation of deuterium-labeled furanone products established heterolytic cleavage followed by the transfer of deuterium from labeled tributylstannane. In contrast, 3-O-methyl derivatives underwent the elimination of bromine or chlorine radicals to give the 2,3-alkene with no incorporation of label in the methyl vinyl ether. More drastic fragmentation occurred with both of the 3-O-methyl-2-tosyloxy epimers to give an aromatized furan derivative with no deuterium label. Contrasting results observed with the present anhydroalditol models relative to our prior studies with analogously substituted nucleoside models have demonstrated that insights from biomimetic chemical reactions can provide illumination of mechanistic pathways employed by ribonucleotide reductases (RNRs) and the MoaA enzyme involved in the biosynthesis of molybdopterin.

2.
J Chem Inf Model ; 55(2): 362-73, 2015 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-24730573

RESUMO

Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.


Assuntos
Antivirais/química , Antivirais/farmacologia , Farmacorresistência Viral/genética , Imidazóis/química , Imidazóis/farmacologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Algoritmos , Sítios de Ligação , Análise por Conglomerados , Simulação por Computador , Genótipo , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutação , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética
3.
ChemMedChem ; 9(9): 2186-92, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24788480

RESUMO

Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral infections, efforts have been made to better understand the mechanisms by which hENT1 modulates nucleoside transport. To that end, we report here the design and synthesis of novel tool compounds for the further study of hENT1. The 7-deazapurine nucleoside antibiotic tubercidin was converted into its 4-N-benzyl and 4-N-(4-nitrobenzyl) derivatives by alkylation at N3 followed by a Dimroth rearrangement to the 4-N-isomer or by fluoro-diazotization followed by SN Ar displacement of the 4-fluoro group by a benzylamine. The 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin antibiotics were prepared by the alkylation approach. Cross-membrane transport of labeled uridine by hENT1 was inhibited to a weaker extent by the 4-nitrobenzylated tubercidin and sangivamycin analogues than was observed with 6-N-(4-nitrobenzyl)adenosine. Type-specific inhibition of cancer cell proliferation was observed at micromolar concentrations with the 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin, and also with 4-N-benzyltubercidin. Treatment of 2',3',5'-O-acetyladenosine with aryl isocyanates gave the 6-ureido derivatives but none of them exhibited inhibitory activity against cancer cell proliferation or hENT1.


Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Transportador Equilibrativo 1 de Nucleosídeo/antagonistas & inibidores , Nucleosídeos de Purina/síntese química , Purinas/síntese química , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Toiocamicina/análogos & derivados , Alquilação , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Moduladores de Transporte de Membrana/síntese química , Moduladores de Transporte de Membrana/farmacologia , Toiocamicina/síntese química , Toiocamicina/farmacologia , Tubercidina/química , Tubercidina/farmacologia
4.
J Biol Chem ; 287(36): 30444-54, 2012 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-22730407

RESUMO

The antimetabolite prodrug 3-deazauridine (3DUrd) inhibits CTP synthetase upon intracellular conversion to its triphosphate, which selectively depletes the intracellular CTP pools. Introduction of a fluorine atom at C3 of 3DUrd shifts its antimetabolic action to inhibition of the orotidylate decarboxylase (ODC) activity of the UMP synthase enzyme complex that catalyzes an early event in pyrimidine nucleotide biosynthesis. This results in concomitant depletion of the intracellular UTP and CTP pools. The new prodrug (designated 3F-3DUrd) exerts its inhibitory activity because its monophosphate is not further converted intracellularly to its triphosphate derivative to a detectable extent. Combinations with hypoxanthine and adenine markedly potentiate the cytostatic activity of 3F-3DUrd. This is likely because of depletion of 5-phosphoribosyl-1-pyrophosphate (consumed in the hypoxanthine phosphoribosyl transferase/adenine phosphoribosyl transferase reaction) and subsequent slowing of the 5-phosphoribosyl-1-pyrophosphate-dependent orotate phosphoribosyl transferase reaction, which depletes orotidylate, the substrate for ODC. Further efficient anabolism by nucleotide kinases is compromised apparently because of the decrease in pK(a) brought about by the fluorine atom, which affects the ionization state of the new prodrug. The 3F-3DUrd monophosphate exhibits new inhibitory properties against a different enzyme of the pyrimidine nucleotide metabolism, namely the ODC activity of UMP synthase.


Assuntos
3-Desazauridina/química , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Carbono-Nitrogênio Ligases/química , Flúor/química , Orotidina-5'-Fosfato Descarboxilase/antagonistas & inibidores , Orotidina-5'-Fosfato Descarboxilase/química , Nucleosídeos de Pirimidina/biossíntese , 3-Desazauridina/análogos & derivados , Animais , Carbono-Nitrogênio Ligases/metabolismo , Halogenação , Células HeLa , Humanos , Camundongos , Orotidina-5'-Fosfato Descarboxilase/metabolismo
5.
Biochem Pharmacol ; 81(1): 82-90, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20854794

RESUMO

Human concentrative nucleoside transporters (hCNTs) mediate electrogenic secondary active transport of physiological nucleosides and nucleoside drugs into cells. Six fused-pyrimidine ribonucleosides and one 2'-deoxynucleoside were assessed for their abilities to inhibit [(3)H]uridine transport in the yeast Saccharomyces cerevisiae producing recombinant hCNT1, hCNT2 or hCNT3. Six of the analogs inhibited hCNT1 with K(i) values<1µM whereas only two analogs inhibited hCNT3 with K(i) values<1µM and none inhibited hCNT2. To assess if the inhibitory analogs were also permeants, currents evoked were measured in oocytes of Xenopus laevis producing recombinant hCNT1, hCNT2 or hCNT3. Significant inward currents, indicating permeant activity, were generated with (i) three of the analogs in hCNT1-producing oocytes, (ii) none of the analogs in hCNT2-producing oocytes and (iii) all of the analogs in hCNT3-producing oocytes. Four were not, or were only very weakly, transported by hCNT1. The thienopyrimidine 2'-deoxynucleoside (dMeThPmR, 3) and ribonucleoside (MeThPmR, 4) were the most active inhibitors of uridine transport in hCNT1-producing oocytes and were an order of magnitude more effective than adenosine, a known low-capacity transport inhibitor of hCNT1. Neither was toxic to cultured human leukemic CEM cells, and both protected CEM cell lines with hCNT1 but not with hENT1 against gemcitabine cytotoxicity. In summary, dMeThPmR (3) and MeThPmR (4) were potent inhibitors of hCNT1 with negligible transportability and little apparent cytotoxicity, suggesting that pending further evaluation for toxicity against normal cells, they may have utility in protecting normal hCNT1-producing tissues from toxicities resulting from anti-cancer nucleoside drugs that enter via hCNT1.


Assuntos
Citoproteção/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Nucleosídeos de Pirimidina/farmacologia , Animais , Antineoplásicos/efeitos adversos , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Leucemia/tratamento farmacológico , Estrutura Molecular , Oócitos , Nucleosídeos de Pirimidina/química , Saccharomyces cerevisiae , Xenopus laevis
6.
J Med Chem ; 53(16): 6040-53, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20718495

RESUMO

5'-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAENTA), 5'-S-(2-acetamidoethyl)-6-N-[(4-substituted)benzyl]-5'-thioadenosine analogues, 5'-S-[2-(6-aminohexanamido)]ethyl-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAHENTA), and related compounds were synthesized by S(N)Ar displacement of fluoride from 6-fluoropurine intermediates with 4-(substituted)benzylamines. Conjugation of the pendant amino groups of SAENTA and SAHENTA with fluorescein-5-yl isothiocyanate (FITC) gave fluorescent probes that bound at nanomolar concentrations specifically to human equilibrative nucleoside transporter 1 (hENT1) produced in recombinant form in model expression systems and in native form in cancer cell lines. Transporter binding effects were studied and the ability of the probes to predict the potential antitumor efficacy of 2'-deoxy-2',2'-difluorocytidine (gemcitabine) was demonstrated.


Assuntos
Adenosina/análogos & derivados , Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/síntese química , Corantes Fluorescentes/síntese química , Tionucleosídeos/síntese química , Adenosina/síntese química , Adenosina/química , Animais , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Transportador Equilibrativo 1 de Nucleosídeo/química , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Humanos , Camundongos , Oócitos/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Tioinosina/análogos & derivados , Tioinosina/farmacologia , Tionucleosídeos/química , Xenopus , Leveduras/efeitos dos fármacos , Leveduras/metabolismo
7.
J Med Chem ; 52(9): 3018-27, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19378989

RESUMO

New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2'-deoxy and arabino analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-2,4(1H,3H)-dione derivatives underwent palladium-catalyzed hydrogenolysis of one C-F bond at atmospheric pressure, and deprotection gave the 3-deaza-3-fluorouracil compounds. Selective reaction of a stabilized Wittig reagent at C4 of the 3,3-difluoro-2,4-dione intermediates gave exocyclic alkenes that underwent hydrogenation accompanied by spontaneous elimination of hydrogen fluoride. Ammonolysis of the exocyclic carbethoxymethyl substituent and ester protecting groups gave 4-(carboxamidomethyl)-3-deaza-3-fluorouridine and its analogues. Grignard additions at C4 of the ribo and 2'-deoxy 3,3-difluoro-2,4-dione intermediates followed by deprotection gave the 3-deaza-3,3-difluoro-4-hydroxy-4-(substituted)uracil nucleosides. The cytostatic activity of 3-fluoro-3-deazauridine (CC(50) = 4.4-9.6 microM) in three cancer cell lines paralleled that of 3-deazauridine, whereas no significant inhibitory activity was observed with a variety of virus-infected cell cultures.


Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Piridonas/química , Animais , Antivirais/síntese química , Linhagem Celular , Halogenação , Humanos , Camundongos , Nucleosídeos/síntese química , Vírus/efeitos dos fármacos
8.
Cancer Res ; 68(7): 2349-57, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18381442

RESUMO

To understand the mechanism of cellular resistance to the nucleoside analogue cytarabine (1-beta-D-arabinofuranosylcytosine, AraC), two resistant derivatives of the human leukemic line CCRF-CEM were obtained by stepwise selection in different concentrations of AraC. CEM/4xAraC cells showed low AraC resistance, whereas CEM/20xAraC cells showed high resistance. Both cell lines showed similar patterns of cross-resistance to multiple cytotoxic nucleoside analogues, with the exception that CEM/20xAraC cells remained sensitive to 5-fluorouridine and 2-deoxy-5-fluorouridine. Both cell lines were sensitive to 5-fluorouracil and to a variety of natural product drugs. Although both CEM/4xAraC and CEM/20xAraC cells displayed reduced intracellular accumulation of [(3)H]AraC, only CEM/4xAraC cells showed reduced uptake of [(3)H]uridine, which was used to assess nucleoside transport activities. Genes encoding proteins known to be involved in nucleoside transport, efflux, and metabolism were analyzed for the presence of mutations in the two cell lines. In CEM/4xAraC cells, independent mutations were identified at each allele of human equilibrative nucleoside transporter 1 (hENT1; SLC29A1), one corresponding to a single-nucleotide change in exon 4, the other being a complex intronic mutation disrupting splicing of exon 13. In contrast to CEM/20xAraC cells, CEM/4xAraC cells did not bind the hENT1/SLC29A1 ligand nitrobenzylmercaptopurine ribonucleoside and lacked detectable hENT1/SLC29A1 protein. In CEM/20xAraC cells, independent intronic mutations impairing splicing of exons 2 and 3 were found at each allele of the deoxycytidine kinase gene. These studies point to at least two distinct mechanisms of AraC resistance in leukemic cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citarabina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/farmacocinética , Citarabina/farmacocinética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Transportador Equilibrativo 1 de Nucleosídeo/biossíntese , Transportador Equilibrativo 1 de Nucleosídeo/genética , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
9.
J Org Chem ; 72(22): 8216-21, 2007 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-17918996

RESUMO

A variant of the semipinacol rearrangement that was observed in our laboratory has been applied to the synthesis of several furanose and pyranose derivatives. The process consists of an "orchestrated" [1,2]-hydride shift with departure of a leaving group from the opposite face. Transient formation of a C=O group is followed by rapid transfer of a hydride-equivalent from the same face from which the leaving group departed, which results in double inversion of stereochemistry at the two vicinal carbon atoms. Treatment of 2'-O- and 3'-O-tosyladenosine with lithium triethylborohydride in DMSO/THF gave the respective 2'- and 3'-deoxynucleoside analogues with beta-D-threo configurations. Identical treatment of 5'-O-TPS-2'-O-tosyladenosine gave 9-(5-O-TPS-2-deoxy-beta-D-threo-pentofuranosyl)adenine. The same [1,2]-hydride shift and stereochemistry with the 5'-OH and 5'-O-TPS compounds demonstrated the absence of remote hydroxyl-group participation. Application of this process to other nucleoside 2'-O-tosyl derivatives gave the 2'-deoxy-threo compounds in good yields. The reaction-rate order was OTs approximately Br >> Cl for 2'-O-tosyladenosine, 2'-bromo-2'-deoxyadenosine, and 2'-chloro-2'-deoxyadenosine (all with beta-d-ribo configurations). Analogous results were obtained with mannopyranoside derivatives with either 4,6-O-benzylidene protection or a free OH group at C4. Deuterium labeling clearly defined the stereochemical course as a cis-vicinal [1,2]-hydride shift on the face opposite to the original cis OH and OTs groups followed by hydride transfer from the face opposite to the [1,2]-hydride shift. Synthetic and mechanistic considerations are discussed.


Assuntos
Desoxirribonucleotídeos/síntese química , Ribonucleotídeo Redutases/química , Ribonucleotídeos/química , Cristalografia por Raios X , Desoxirribonucleotídeos/química , Elétrons , Modelos Moleculares , Conformação Molecular , Oxirredução , Estereoisomerismo
10.
J Med Chem ; 50(16): 3897-905, 2007 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-17622128

RESUMO

Sonogashira coupling strategies were employed to synthesize new furo[2,3-d]pyrimidin-2(3H)-one (FuPyrm) 2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl- and ethyl-linked derivatives. Levels of inhibition of varicella-zoster virus (VZV), human cytomegalovirus (HCMV), a broad range of other DNA and RNA viruses, and several cancer cell lines were evaluated in cell cultures. The anti-VZV potency decreased with increasing rigidity of the side chain at C6 of the FuPyrm ring in the order dec-1-yn-1-yl < dec-1-en-1-yl < decan-1-yl. In contrast, compounds with a rigid ethynyl spacer between C6 of the FuPyrm ring and a 4-alkylphenyl moiety were more potent inhibitors of VZV than the corresponding derivatives with an ethyl spacer. Replacement of the phenyl moiety in 6-(4-alkylphenyl) derivatives with a pyridine ring (in either regioisomeric orientation) gave analogues with increased solubility in methanol but reduced anti-VZV potency, and replacement with a pyrimidine ring reduced the anti-VZV activity even further. The pyridine-ring-containing analogues were approximately 20-fold more potent inhibitors of VZV than acyclovir but were approximately 6-fold less potent than BVDU and approximately 60-fold weaker than the most active 6-(4-pentylphenyl)-substituted prototype.


Assuntos
Antivirais/síntese química , Furanos/síntese química , Nucleosídeos de Pirimidina/síntese química , Alcenos/síntese química , Alcenos/química , Alcenos/farmacologia , Alquinos/síntese química , Alquinos/química , Alquinos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Cristalografia por Raios X , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Vírus de DNA/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/genética , Humanos , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Vírus de RNA/efeitos dos fármacos , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Timidina Quinase/genética
11.
J Am Chem Soc ; 129(18): 5962-8, 2007 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-17439120

RESUMO

SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides and nitrogen, oxygen, and sulfur nucleophiles were studied. Pseudo-first-order kinetics were measured with 6-halopurine compounds, and comparative reactivities were determined versus a 6-(alkylsulfonyl)purine nucleoside. The displacement reactivity order was: F > Br > Cl > I (with BuNH2/MeCN), F > Cl approximately Br > I (with MeOH/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)/MeCN), and F > Br > I > Cl [with K+ -SCOCH3/dimethyl sulfoxide (DMSO)]. The order of reactivity with a weakly basic arylamine (aniline) was: I > Br > Cl > F (with 5 equiv of aniline in MeCN at 70 degrees C). However, those reactions with aniline were autocatalytic and had significant induction periods ( approximately 50 min for the iodo compound and approximately 6 h for the fluoro analogue). Addition of trifluoroacetic acid (TFA) eliminated the induction period, and the order then was F > I > Br > Cl (with 5 equiv of aniline and 2 equiv of TFA in MeCN at 50 degrees C). The 6-(alkylsulfonyl)purine nucleoside analogue was more reactive than the 6-fluoropurine compound with both MeOH/DBU/MeCN and iPentSH/DBU/MeCN and was more reactive than the Cl, Br, and I compounds with BuNH2 and aniline/TFA. Titration of the 6-halopurine nucleosides in CDCl3 with TFA showed progressive downfield 1H NMR chemical shifts for H8 (larger) and H2 (smaller). The major site of protonation as N7 for both the 6-fluoro and 6-bromo analogues was confirmed by large upfield shifts ( approximately 16 ppm) of the 15N NMR signal for N7 upon addition of TFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented.


Assuntos
Halogênios/química , Nucleosídeos de Purina/síntese química , Cinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Nucleosídeos de Purina/química
12.
J Org Chem ; 72(9): 3319-25, 2007 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-17385920

RESUMO

Syntheses of 3'-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane ring fused at C3'-C4' are described. Treatment of a 2',5'-protected-3',4'-unsaturated derivative of uridine with difluorocarbene [generated from (CF3)2Hg and NaI] gave a diastereomeric mixture of the 3',4'-difluoromethylene compounds (alpha-L-arabino/beta-D-ribo, approximately 5:4). The limited stereoselectivity for addition at the beta face results from competitive steric hindrance by an allylic 4-methoxybenzyloxy group at C2' on the alpha face and a homoallylic nucleobase at C1' on the beta face. Protected uracil derivatives were converted into their cytosine counterparts via 4-(1,2,4-triazol-1-yl) intermediates. Treatment of 1,2-dihydrofurans derived from D- and L-xylose with difluorocarbene resulted in stereospecific addition at the beta face (anti to the 1,2-O-isopropylidene group on the alpha face). Glycosylations with activated enantiomeric sugar derivatives with the fused difluorocyclopropane ring on the beta face gave protected adenine nucleosides, whereas attempted glycosylation with an alpha-fused derivative gave multiple products. Removal of base- and sugar-protecting groups gave new difluoromethylene-bridged nucleoside analogues.


Assuntos
Química Orgânica/métodos , Hexanos/química , Hidrocarbonetos Fluorados/química , Nucleosídeos/química , Uridina/química , Xilose/química , Cristalografia por Raios X , Citosina/química , Furanos/química , Glicosilação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo
13.
J Biol Chem ; 282(19): 14148-57, 2007 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-17379602

RESUMO

Equilibrative nucleoside transporters (ENTs) are important for the metabolic salvage of nucleosides and the cellular uptake of antineoplastic and antiviral nucleoside analogs. Human equilibrative nucleoside transporter 1 (hENT1) is inhibited by nanomolar concentrations of structurally diverse compounds, including dipyridamole, dilazep, nitrobenzylmercaptopurine ribonucleoside (NBMPR), draflazine, and soluflazine. Random mutagenesis and screening by functional complementation for inhibitor-resistant mutants in yeast revealed mutations at Phe-334 and Asn-338. Both residues are predicted to lie in transmembrane segment 8 (TM 8), which contains residues that are highly conserved in the ENT family. F334Y displayed increased V(max) values that were attributed to increased rates of catalytic turnover, and N338Q and N338C displayed altered membrane distributions that appeared to be because of protein folding defects. Mutations of Phe-334 or Asn-338 impaired interactions with dilazep and dipyridamole, whereas mutations of Asn-338 impaired interactions with draflazine and soluflazine. A helical wheel projection of TM 8 predicted that Phe-334 and Asn-338 lie in close proximity to other highly conserved and/or hydrophilic residues, suggesting that they form part of a structurally important region that influences interactions with inhibitors, protein folding, and rates of conformational change during the transport cycle.


Assuntos
Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Compostos Heterocíclicos/farmacologia , Conformação Proteica , Dobramento de Proteína , Adenosina/metabolismo , Sequência de Aminoácidos , Transporte Biológico , Dilazep/farmacologia , Transportador Equilibrativo 1 de Nucleosídeo/química , Transportador Equilibrativo 1 de Nucleosídeo/genética , Teste de Complementação Genética , Humanos , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Mutagênese , Mutação , Nucleosídeos/farmacologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Homologia de Sequência de Aminoácidos , Tioinosina/farmacologia
14.
J Org Chem ; 72(7): 2678-81, 2007 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-17335236

RESUMO

Bromo- and iodoalkenes undergo trifluoromethylation efficiently in DMA with "CF3Cu" generated from (CF3)2Hg and Cu. Variable stereochemical inversion is observed with substrates having a gem-carbonyl group. Substrates having gem-hydrogen, -alkyl, or -alkenyl groups give products with stereochemical retention.


Assuntos
Alcenos/química , Brometos/química , Flúor/química , Iodetos/química , Compostos Organometálicos/química , Uracila/química , Metilação , Estrutura Molecular
15.
J Org Chem ; 72(2): 532-7, 2007 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-17221971

RESUMO

Treatment of protected 2'-deoxy-3',4'-unsaturated nucleosides derived from adenosine and uridine with difluorocarbene [generated from bis(trifluoromethyl)mercury and sodium iodide] gave fused-ring 2,2-difluorocyclopropane compounds. Stereoselective alpha-face addition to the dihydrofuran ring resulted from hindrance by the protected beta-anomeric nucleobases. A protected uracil compound was converted smoothly into the cytosine derivative via a 4-(1,2,4-triazol-1-yl) intermediate. Removal of the protecting groups gave new difluorocyclopropane-fused nucleoside analogues. The solid-state conformation of the nearly planar furanosyl ring in the uracil compound had a shallow 2E pucker, and a more pronounced 1E conformation was present in the furanosyl ring of the cytosine derivative.


Assuntos
Compostos Bicíclicos com Pontes/química , Cicloexanos/química , Hidrocarbonetos Fluorados/química , Nucleosídeos/química , Nucleosídeos/síntese química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular
16.
J Org Chem ; 71(23): 8876-83, 2006 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-17081018

RESUMO

Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.


Assuntos
Adenosina/análogos & derivados , Citidina/análogos & derivados , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Nucleosídeos/síntese química , Oxigênio/química , Compostos de Espiro/síntese química , Uridina/análogos & derivados , Adenosina/síntese química , Cristalografia por Raios X , Citidina/síntese química , Modelos Moleculares , Conformação Molecular , Nucleosídeos/química , Estereoisomerismo , Uridina/síntese química
17.
J Org Chem ; 71(23): 8901-6, 2006 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-17081021

RESUMO

Purine alkylations have been plagued with formation of mixtures of N9 (usually desired), N7, and other regioisomers. We have developed methods for synthesis of 6-(azolyl)purine derivatives whose X-ray crystal structures show essentially coplanar conformations of the linked azole-purine rings. Such ring orientations position the C-H of the azole above N7 of the purine, which results in protection of N7 from alkylating agents. Treatment of 6-(2-butylimidazol-1-yl)-2-chloropurine (9) with sodium hydride in DMF followed by addition of ethyl iodide resulted in exclusive formation of 6-(2-butylimidazol-1-yl)-2-chloro-9-ethylpurine (10), whereas identical treatment of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (11) produced a regioisomeric mixture 12/13 (N9/N7, approximately 5:1). The linked imidazole and purine rings are coplanar in 9 (the butyl side chain is extended away from the purine ring and C-H is over N7) but are rotated approximately 57 degrees in 11, and the more bulky azole substituent in 11 did not prevent formation of the minor N7 regioisomer 13. Access to various regioisomerically pure 9-alkylpurines is now readily available.


Assuntos
Imidazóis/síntese química , Purinas/síntese química , Alquilação , Estrutura Molecular , Purinas/química , Estereoisomerismo
18.
J Org Chem ; 71(20): 7773-9, 2006 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-16995685

RESUMO

Glycosylation of 6-(substituted-imidazol-1-yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-alpha-D-erythro-pentofuranosyl chloride proceeds with regiospecific formation of the N9 isomers. Base substrates with lipophilic substituents on the C6-linked imidazole moiety are more soluble in organic solvents, and the solubility is further increased with binary solvent mixtures. Selective solvation also diminishes the extent of anomerization of the chlorosugar. Stirred reaction mixtures of the modified-purine sodium salts generated in a polar solvent and cooled solutions of the protected 2-deoxysugar chloride in a nonpolar solvent give 2'-deoxynucleoside derivatives with N9 regiochemistry and enhanced beta/alpha configuration ratios. Application of the binary-solvent methodology with 2-chloro-6-(substituted-imidazol-1-yl)purine salts in cold acetonitrile and the chlorosugar in cold dichloromethane gives essentially quantitative yields of the N9 isomers of beta-anomeric 2'-deoxynucleoside intermediates. Direct ammonolysis (NH(3)/MeOH) of such intermediates or benzylation of the imidazole ring followed by milder ammonolysis of the imidazolium salt gives high yields of the clinical anticancer drug cladribine (2-chloro-2'-deoxyadenosine).


Assuntos
Carboidratos/química , Cladribina/síntese química , Purinas/química , Antineoplásicos/síntese química , Glicosilação , Solventes , Estereoisomerismo
19.
Org Lett ; 8(20): 4565-8, 2006 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-16986951

RESUMO

Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in pyrimidine ring opening followed by exocyclic ring closure. Ammonolysis gave 5-amino-4-(5-substituted-1,2,4-oxadiazol-3-yl)-1-(beta-d-ribofuranosyl)imidazole derivatives, whereas iodine in methanol selectively unmasked the 5-amino group. Related flexible nucleoside analogues can be prepared from adenine-type precursors.


Assuntos
Adenosina/química , Imidazóis/química , Nucleosídeos/química , Óxidos/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares
20.
J Biol Chem ; 281(38): 28210-21, 2006 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-16854981

RESUMO

The uptake of Urd into the yeast Saccharomyces cerevisiae is mediated by Fui1p, a Urd-specific nucleoside transporter encoded by the FUI1 gene and a member of the yeast Fur permease family, which also includes the uracil, allantoin, and thiamine permeases. When Fui1p was produced in a double-permease knock-out strain (fur4Deltafui1Delta) of yeast, Urd uptake was stimulated at acidic pH and sensitive to the protonophore carbonyl cyanide m-chlorophenylhydrazone. Electrophysiological analysis of recombinant Fui1p produced in Xenopus oocytes demonstrated that Fui1p-mediated Urd uptake was dependent on proton cotransport with a 1:1 stoichiometry. Mutagenesis analysis of three charged amino acids (Glu(259), Lys(288), and Asp(474) in putative transmembrane segments 3, 4, and 7, respectively) revealed that only Lys(288) was required for maintaining high Urd transport efficiency. Analysis of binding energies between Fui1p and different Urd analogs indicated that Fuip1 interacted with C(3')-OH, C(2')-OH, C(5)-H, and N(3)-H of Urd. Fui1p-mediated transport of Urd was inhibited by analogs with modifications at C-5', but was not inhibited significantly by analogs with modifications at C-3', C-5, and N-3 or inversions of configuration at C-2' and C-3'. This characterization of Fui1p contributes to the emerging knowledge of the structure and function of the Fur family of permeases, including the Fui1p orthologs of pathogenic fungi.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Animais , Concentração de Íons de Hidrogênio , Proteínas de Membrana Transportadoras/química , Proteínas de Transporte de Nucleosídeos , Transporte Proteico , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/química , Relação Estrutura-Atividade , Uridina/metabolismo , Xenopus
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