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PubMed1996

New carbamate supports for the preparation of 3'-amino-modified oligonucleotides.

A novel approach for the preparation of oligonucleotides carrying amino groups at the 3'-end is described. Several CPG supports having aminoalkyl groups and 3'-amino-2',3'-dideoxynucleosides linked through base-labile carbamate linkages such as 2-(2-nitrophenyl)ethoxycarbonyl and fluorenylmethoxycarbonyl were prepared using two different strategies. These supports are compatible to the standard solid phase phosphite-triester methodology and yield oligonucleotides containing amino groups at the 3'-end. Several properties of the 3'-amino oligonucleotides, such as nuclease resistance, hybridization, and preparation of oligonucleotide conjugates are discussed.

Carbamates↗
PubMed2004

Synthesis of D- and L-apio nucleoside analogues with 2'-hydroxyl group as potential anti-HIV agents.

The present work describes the asymmetric synthesis of D- and L-apio-2',3'-dideoxynucleoside analogues, 4 and 5 with 2'-hydroxyl group via a common intermediate 9, starting from D-galactose. Stereoselective dihydroxylation and deoxygenation through radical inversion were successfully employed to synthesize the key intermediate 12 with D-apio structure, while stereoselecetive hydroboration-oxidation was used for the synthesis of another key intermediate 18 with L-apio structure.

Anti-HIV Agents↗
PubMed2006

The incorporation of nucleoside analogs by human immunodeficiency virus type 1 reverse transcriptase decreases in the presence of polyamines.

Nucleoside analogs (NAs) are an important class of anti-retroviral compounds used against human immunodeficiency virus (HIV). We have analyzed the potential effect of polyamines on the incorporation of NAs during DNA synthesis by HIV type-1 (HIV-1) reverse transcriptase (RT). The polyamines exert the ability to decrease the incorporation of various dideoxynucleoside triphosphates (ddATP, ddTTP or ddCTP) with both RNA/DNA and DNA/DNA substrates in the following order: spermine>spermidine>putrescine. The reduction is a sequence-independent effect, taking place at different sequence context. The results suggest that polyamines might affect the inhibition of reverse transcription by nucleoside analogs HIV-1 RT directed.

DNA, Complementary↗
PubMed1989

Estimation of the lipophilicity of anti-HIV nucleoside analogues by determination of the partition coefficient and retention time on a Lichrospher 60 RP-8 HPLC column.

There is a close linear correlation between the log partition coefficient (Pa) of a series of 2'-deoxyriboside (dR), 2',3'-didehydro-3'-dideoxyriboside (ddeR), 2',3'-dideoxyriboside (ddR), 3'-fluoro-2',3'-dideoxyriboside (FddR) and 3'-azido-2',3'-dideoxyriboside (AzddR) derivatives of uracil, cytosine, thymine, guanine, adenine and 2,6-diaminopurine and their retention times (Rt) on a Lichrospher 60 RP-8 HPLC column (correlation coefficient r greater than 0.970). Within each class of compounds the following order of increasing lipophilicity was noted: dR less than ddeR less than ddR less than FddR less than AzddR. A straight-forward structure-lipophilicity relationship for both base and sugar modified purine and pyrimidine 2',3'-dideoxynucleosides could be delineated.

Antiviral Agents↗
PubMed1997

Lamivudine (3TC) phosphorylation and drug interactions in vitro.

Lamivudine (2'-deoxy-3'-thiacytidine; 3TC) is a dideoxynucleoside analogue that inhibits the replication of human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of 3TC to its active triphosphate (3TCTP) in peripheral blood mononuclear cells (PBMC) and a monocytic cell line (U937). Optimal phosphorylation of 3TC was achieved after incubation for 24 hr, with 3TC diphosphate (3TCDP) the predominant metabolite formed, in both cell types investigated. Further studies in PBMCs followed preincubation with the mitogen phytohaemagglutinin (PHA) for 72 hr. This enabled greater detection of phosphates, compared to resting cells. A 3TC concentration of 1 microM was chosen for future interaction studies, allowing good detection of 3TC and phosphates on radiochromatograms whilst being similar to the plasma level found in clinical studies (i.e. 3 microM). With a shift in treatment to combination therapy, it is essential that potential interactions between nucleoside analogues are investigated at the phosphorylation level, as this could affect antiviral activity. Both deoxycytidine (dC) and 2',3'-dideoxycytidine (ddC) significantly inhibited 3TC phosphorylation (e.g. at dC 100 microM, no 3TCTP was detected in PBMCs; P < 0.001, whereas 66% of control 3TCTP production was observed in U937 cells; P < 0.01). Zidovudine (ZDV) caused a small but significant reduction of 3TC phosphate production in both PBMCs and U937 cells. However, this may be due to toxicity or an effect on endogenous dCTP pools. Neither 2',3'-dideoxyinosine (ddI) or 2',3'-didehydro-2',3'-dideoxythymidine (d4T) significantly inhibited 3TC phosphorylation. These results suggest it would be better to coadminister two nucleoside analogues with different activation pathways.

Anti-HIV Agents↗
PubMed1997

Conformational analysis of the complete series of 2' and 3' monofluorinated dideoxyuridines.

The solution conformations of a set of uridine 2',3'-dideoxynucleosides, where each of the hydrogens at the 2'- and 3'-positions of the sugar ring were individually replaced with a fluorine atom, were studied by nuclear magnetic resonance spectroscopy and pseudorotational analysis. The distribution of the north/south (N/S) puckering equilibrium for each compound was calculated by coupling constant analysis aided by the program PSEUROT. The data confirmed that the pseudorotational equilibrium of the fluorinated glycones is governed by the position of the fluorine atom. The preferred rotamer populations about the C4'-C5' (gamma) and C1'-N1' (chi) bonds calculated from coupling constant and NOE analysis, respectively, were also influenced by the presence of fluorine. Proton coupling to the fluorine atom was also used to qualitatively estimate the N/S equilibrium population. Through space, long range 1H-19F coupling constants were observed in compounds where the fluorine atom was above the plane of the ring ('up'). The pseudorotational parameters of the compounds described were tempered by the anomeric effect which drives the pseudorotational equilibrium towards the 2'-exo/3'-endo (northern) pucker. Ab initio calculations using the 3-21 G* basis set yielded a measure of the energy differences between the N and S local minima in each compound. These results agree with previous conformational studies of other fluorinated nucleoside analogues and prove that the furanose ring pucker is governed by the highly electronegative fluorine atom. However, the competing anomeric effect plays a major role in determining the mole fraction of the minor conformer of these compounds in solution.

Dideoxynucleosides↗
PubMed1999

Correlation of anti-HIV activity with structure: use of electrostatic potential and conformational analysis.

Electrostatic potential distribution, 3-D electron density shapes, and conformational analysis were used to correlate anti-HIV activity or inactivity of AZT, (-) carbovir, oxetanocin A, and 16 isomeric dideoxynucleosides of different families. The structure-activity profile discovered is significant and is expected to contribute to the development of a much needed predictive QSAR analysis in this area.

Adenine↗
PubMed1990

Metabolism of the carbocyclic nucleoside analogue carbovir, an inhibitor of human immunodeficiency virus, in human lymphoid cells.

Carbovir (CBV) is a highly selective carbocyclic nucleoside inhibitor of HIV replication in human lymphocytes and is potentially useful in the treatment of AIDS [Vince et al. (1988) Biochem. Biophys. Res. Commun. 156, 1046-1053]. Using human lymphoid cells severely deficient in nucleoside kinases, we were able to identify the route of activation of CBV metabolism. The present studies have demonstrated that CBV is anabolized to the mono-, di-, and triphosphates and to guanosine 5'-triphosphate in CCRF-CEM cells. Conversion to GTP amounted to 15-20% of the total analogue nucleotides formed in the cells and may arise from CBV through depurination and salvage via HGPRT. Evidence was obtained that neither deoxycytidine kinase, adenosine kinase, or mitochondrial deoxyguanosine kinase is primarily involved in the initial step of phosphorylation of CBV in CCRF-CEM cells. In contrast, earlier studies [Johnson & Fridland (1989) Mol. Pharmacol. 36, 291-295] showed that a cytosolic 5'-nucleotidase catalyzes the activation of CBV to the monosphosphate. Other biochemical effects examined showed that the nucleobases hypoxanthine and adenine, but not guanine, their respective nucleosides, and the dideoxynucleosides 2',3'-dideoxyinosine, 2',3'-dideoxyguanosine, and 3'-azido-3'-deoxythymidine produced significant increased accumulation of CBV nucleotides in CEM cells. The exact mechanism for this potentiation of CBV phosphorylation has not been elucidated but may be due to a modulating effect of intracellular nucleotides on 5'-nucleotidase activity.

5'-Nucleotidase↗
PubMed2001

Syntheses and structure--activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents.

On the basis of the fact that apio dideoxynucleosides, in which the furanose oxygen and the C2 of the 2,3-dideoxyribose are transposed, exhibited potent anti-HIV activity and 2',3'-dideoxy-2',3'-didehydronucleosides also showed potent anti-HIV activity, we synthesized apio dideoxydidehydronucleosides in which the oxygen atom and the double bond of the 2,3-dideoxy-2,3-didehydroribose are exchanged. The thioapio dideoxydidehydronucleosides were also synthesized since sulfur serves as a bioisostere of oxygen. Apio dideoxydidehydronucleosides 13a--f were synthesized starting from 1,3-dihydroxyacetone, utilizing phenylselenenyl chemistry as a key step. The ratio of the anomeric mixture was variable from 1:1 to 5:1 during the condensation of nucleosidic bases with the phenylselenyl acetate 11 in the presence of a Lewis acid. This is in contrast with other glycosyl donors such as 5-O-(tert-butyldiphenylsilyl)-2-phenylselenenyl-2,3-dideoxyribosyl acetate which shows excellent neighboring group effect (alpha:beta = 1:99). Thioapio dideoxydidehydronucleosides 22a,b were synthesized from the lactone 9 via thiolactone 17 as a key intermediate which was synthesized from dicyclohexylcarbodiimide coupling of the mercapto acid produced from the basic hydrolysis of thioacetate 16. The majority of apio analogues synthesized in this study exhibited moderate to potent anti-HCMV activity, among which the 5-fluorouracil derivative 13c was found to be the most potent against HCMV, while thioapio analogues showed no activity against HCMV. However, all synthesized compounds did not exhibit any significant activities against HIV-1, HSV-1, and HSV-2. The fact that apio dideoxydidehydronucleosides were active against HCMV suggests that the apio dideoxydidehydro sugar moiety can serve as a novel template for the development of new antiviral agents.

Antiviral Agents↗
PubMed2003

Enantioselective syntheses and cytotoxicity of N,O-nucleosides.

Enantiomers of 4'-aza-2',3'-dideoxynucleosides have been prepared by two different synthetic approaches, on the basis of 1,3-dipolar cycloaddition of a chiral nitrone. Cytotoxicity and apoptotic activity have been investigated. (5'S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(-)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.

Antineoplastic Agents↗
PubMed1994

Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not.

Analysis of the three-dimensional structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) complexed with double-stranded DNA indicates that while many nucleoside-resistance mutations are not at the putative dNTP binding site, several are in positions to interact with the template-primer. Wild-type HIV-1 RT and two nucleoside-resistant variants, Leu74-->Val and Glu89-->Gly, have been analyzed to determine the basis of resistance. The ability of the wild-type enzyme to incorporate, or reject, a 2',3'-dideoxynucleoside triphosphate (ddNTP) is strongly affected by interactions that take place between the enzyme and the extended template strand 3-6 nt beyond the polymerase active site. Inspection of a model of the enzyme with an extended template suggests that this interaction involves the fingers subdomain of the p66 subunit in the vicinity of Leu74. These data provide direct evidence that the fingers subdomain of the p66 subunit of HIV-1 RT interacts with the template strand. The wild-type enzyme is resistant to ddITP if the template extension is 3 nt or less and becomes sensitive only when the template extends more than 3 or 4 nt beyond the end of the primer strand. However, the mutant enzymes are resistant with both short and long template extensions. Taken together with the three-dimensional structure of HIV-1 RT in complex with double-stranded DNA, these data suggest that resistance to the dideoxynucleotide inhibitors results from a repositioning or change in the conformation of the template-primer that alters the ability of the enzyme to select or reject an incoming dNTP.

Base Sequence↗
PubMed2001

Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an alpha-boranophosphate nucleoside analogue.

The amino acid change K65R in human immunodeficiency virus type 1-reverse transcriptase (RT) confers viral resistance to various 2',3'-dideoxynucleoside drugs in vivo. Using pre-steady state kinetic methods, we found that K65R-reverse transcriptase is 3.2-14-fold resistant to 2',3'-dideoxynucleotides in vitro relative to wild-type reverse transcriptase, in agreement with resistance levels observed in vivo. A decreased catalytic rate constant k(pol) mostly accounts for the lower incorporation efficiency observed for 2',3'-dideoxynucleotides. Examination of the crystal structure of the RT.DNA.dNTP complex suggested that both the charge at position 65 and the 3'-OH of the incoming nucleotide act in synergy during the creation of the phosphodiester bond, resulting in a more pronounced decreased catalytic rate constant for 2',3'-dideoxynucleotides than for dNTPs. This type of intramolecular activation of the leaving phosphate by the 3'-OH group appears to be conserved in several nucleotide phosphotransferases. These data were used to design dideoxynucleotide analogues targeting K65R RT specifically. alpha-Boranophosphate ddATP was found to be a 2-fold better substrate than dATP and inhibited DNA synthesis by K65R RT 153-fold better than ddATP. This complete suppression of drug resistance at the nucleotide level could serve for other reverse transcriptases for which drug resistance is achieved at the catalytic step.

Amino Acid Substitution↗
PubMedDate not supplied

Synthesis of novel isomeric dideoxydidehydronucleosides.

Methodologies for the synthesis of novel isomeric dideoxynucleosides with unsaturation in the carbohydrate moiety have been developed. An example of the synthesis (Isod4A) is presented. Antiviral studies are in progress.

Crystallography, X-Ray↗
PubMed1992

Computer-assisted structure-activity correlations of halodideoxynucleoside analogs as potential anti-HIV drugs.

Analysis of the structure-anti-HIV activity correlations of halo dideoxynucleosides (ddN's) in the public domain was accomplished through computer substructure searching, retrieval and sorting of in vitro anti-HIV data. In the survey, selectivity index (ratio of cytotoxicity to the potency in inhibiting HIV replication in vitro) was used to rank compounds in congeneric groups. Factors contributing to the anti-HIV activity, e.g. the nature and location of the halogen on the sugar or the base and its stereochemical configuration, could not be generalized for all the halogenated ddN's. Conclusions were drawn for specific classes within the pyrimidine and purine series, with compounds further divided into halo substitutions at the sugar 2',3',4'-positions or in the pyrimidine or purine ring systems. At the 3'-position, only a fluoro substitution enhanced the activity of the dideoxypyrimidine nucleosides. A 2'-ara fluoro substituent increased the activity of purine ddN's but decreased activity of pyrimidine ddN's. Halogenation of the side chain in acyclic adenine and 2,6-diaminopurine nucleosides improved their anti-HIV activity. Halo substitution at the 6- or 2'-ara position of selected purine ddN's resulted in compounds with increased lipophilicity, chemical stability and retention of anti-HIV activity. The number of halodideoxynucleosides tested as anti-HIV reagents suggested that this class of compounds is well studied.

Antiviral Agents↗