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J L Barascut

Publications and source records attributed to J L Barascut.

16 recordsLinked to original sources
PubMed2003

Synthesis of 3'-deoxy-3'-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-dipolar cycloaddition.

The synthesis of new 3'-deoxy-3'-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]-thymidine 6a-f, from 3'-azido-3'-deoxy-5'-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a-f. All new derivatives 6a-f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found.

Anti-HIV Agents↗
PubMed2000

Synthesis, conformational analysis, and biological activity of C-thioribonucleosides related to tiazofurin.

The syntheses of furanthiofurin [5beta-D-(4'-thioribofuranosyl)furan-3-carboxamide, 1] and thiophenthiofurin [5beta-D-(4'-thioribofuranosyl)thiophene-3-carboxamide, 2], two C-thioribonucleoside analogues of tiazofurin, are described. Direct trifluoroacetic acid-catalyzed C-glycosylation of ethyl furan-3-carboxylate with 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of alpha and beta anomers. Ethyl 5-(2,3,5-tri-O-benzyl)-beta-D-(4'-thioribofuranosyl)furan-3-carboxylate (6beta) was debenzylated and then converted into the corresponding amide (furanthiofurin) by reaction with ammonium hydroxide. A similar C-glycosylation of ethyl thiophene-3-carboxylate with 1,2,3,5-tetra-O-acetyl-4-thio-D-ribofuranose catalyzed by stannic chloride afforded an anomeric mixture of 2- and 5-glycosylated regioisomers. Deacetylation of ethyl 5-(2,3,5-tri-O-acetyl)-beta-D-(4'-thioribofuranosyl)thiophene-3-carboxylate (13beta) with methanolic ammonia and treatment of the ethyl ester with ammonium hydroxide gave thiophenthiofurin. The glycosylation site and anomeric configuration were established by (1)H NMR spectroscopy. Thiophenthiofurin was found to be cytotoxic in vitro toward human myelogenous leukemia K562, albeit 39-fold less than thiophenfurin, while furanthiofurin proved to be inactive. K562 cells incubated with thiophenthiofurin resulted in inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) and an increase in IMP pools with a concurrent decrease in GTP levels. From computational studies it was deduced that, among the C-nucleoside analogues of tiazofurin, activity requires an electrophilic sulfur adjacent to the C-glycosidic bond and an energetically favorable conformer around chi = 0 degrees. Among these, the more constrained (least flexible) compounds (tiazofurin and thiophenfurin) are more active than the less constrained thiophenthiofurin. Those compounds which contain a nucleophilic oxygen in place of the thiazole or thiophene (oxazofurin, furanfurin, and furanthiofurin) show the least activity.

Antineoplastic Agents↗
PubMed1995

4'-Thio-RNA: synthesis of mixed base 4'-thio-oligoribonucleotides, nuclease resistance, and base pairing properties with complementary single and double strand.

4'-Thio-beta-D-oligoribonucleotides (12 mer and 16 mer) containing a mixed base sequence were synthesized via the phosphoramidite solid support approach. These RNA analogs showed very good nuclease resistance as compared with wild-type RNA. Furthermore, 4'-thio-beta-D-oligoribonucleotides were shown to hybridize with a complementary DNA or RNA strand to form a duplex or with a DNA hairpin to form a triple helix. 4'-Thio-RNA binds more tightly to its complementary RNA strand than to its complementary DNA strand. A 4'-thio-RNA:RNA duplex is as stable as a 2'-O-methyl-RNA:RNA duplex. 4'-Thio-RNA, however, forms a 4'-thio-RNA:DNA:DNA triplex with a stability similar to the corresponding triplex with all wild-type DNA.

Amides↗
PubMed1993

4'-Thio-oligo-beta-D-ribonucleotides: synthesis of beta-4'-thio-oligouridylates, nuclease resistance, base pairing properties, and interaction with HIV-1 reverse transcriptase.

We present the synthesis and the study of properties of a new series of modified oligonucleotides, namely 4'-thio-oligo-beta-D-ribonucleotides (4'-S-RNA). Homo-oligonucleotides of this class (4'-SU6 and 4'-SU12) were prepared from the previously known thionucleosides using the phosphoramidite methodology. The comparison of the substrate properties of 4'-SU6 and its natural analog U6 with respect to four nucleases indicates that the former is much more resistant than the latter. Such resistance to nucleases in addition to relatively high Tm values for 4'-SU12 hybridized with Poly(A) show that these new 4'-S-RNA are good candidates for potential antisense effects. The oligonucleotides 4'-SU6 and 4'-SU12 have been also evaluated as non sequence specific inhibitors of HIV-1 reverse transcriptase. All available evidences, based primarily on fluorescence measurements, are consistent with the binding of 4'-SU6 and 4'-SU12 to RT at a site which is different from the polymerase site of the enzyme.

Animals↗
PubMed1992

Sugar modified oligonucleotides: synthesis, nuclease resistance and base pairing of oligodeoxynucleotides containing 1-(4'-thio-beta-D-ribofuranosyl)-thymine.

XdT12 and dT5XdT6, where X is 1-(4'-thio-beta-d-ribofuranosyl)-thymine, were synthesized. The first oligonucleotide presents a better stability against calf spleen phosphodiesterase than natural dT12. The second one hybridizes with complementary sequence. However the X:A base pairing stability is lower than natural T:A one.

Animals↗
PubMed1989

Pathways and kinetics of aqueous decomposition and carbamoylating activity of new anticancer nitroimidazole-linked 2-chloroethylnitrosoureas.

The products of decomposition in anaerobic aqueous solution at pH 7.1 and 37 degrees were determined for two series of novel anticancer agents incorporating both nitroimidazole and 2-chloroethylnitrosourea moieties (NI-CENUs) and examples of which exhibit preferential hypoxic toxicity against HeLa-MR cells. The decomposition products identified were vinyl chloride, acetaldehyde, 2-chloroethanol, ethylene glycol and imidazole-bearing compounds of the type including oxazolidinone, ethylamine or urea moieties. Series A NI-CENUs, which contain a 2-hydroxypropyl unit, gave rise to the oxazolidinone intramolecularly compared with the series B agents which gave rise to the imidazole-ethylamine and ureas. The half-lives of the B series agents were comparable with those of 1,3-bis(2-chloroethyl)nitrosourea (BCNU), 2-cyclohexyl-1-(2-chloroethyl)-1-nitrosourea (CCNU) and streptozotocin. The carbamoylation activity of the series B agents was approximately ten times that of series A compounds. This latter property may be related to the greater potency of series B than series A NI-CENUs against Mer+ HeLa-S3 cells via inhibition of relevant repair enzymes.

Antineoplastic Agents↗
PubMed1989

Chemosensitization at reduced nitroimidazole concentrations by mixed-function compounds combining 2-nitroimidazole and chloroethylnitrosourea.

A mixed-function compound (I-278) combining 2-nitroimidazole and chloroethylnitrosourea has been shown to be greater than 2-fold more toxic to hypoxic HeLa-MR cells than to cells similarly exposed under aerobic conditions, consistent with chemosensitization of nitrosourea toxicity by the 2-nitroimidazole Misonidazole (MISO). However, in the case of I-278, the enhancement resulted from micromolar concentrations of 2-nitroimidazole as opposed to the millimolar quantities required for a similar enhancement by MISO. These experiments provide evidence (1) that the enhanced hypoxic toxicity of I-278 is not attributable to additional, independent hypoxic cell killing by the nitroimidazole group and (2) that the interaction between the two functions under hypoxic conditions results in increased crosslink formation typical of chemosensitization. The data strongly suggest that the chemosensitizing efficiency of nitroimidazoles can be dramatically improved by covalent linkage to a chloroethylating species.

Cell Survival↗
PubMed1988

Aerobic and hypoxic toxicity of a new class of mixed-function drugs associating nitroimidazoles and chloroethylnitrosourea in nitrosourea-sensitive (Mer-) and -resistant (Mer+) human tumor cells.

The cytotoxicity of two series (A and B) of novel mixed-function compounds (NI-CENU) combining nitroimidazole (NI) and chloroethylnitrosourea (CENU) functions were examined in Mer- HeLa-MR and Mer+ HeLa-S3 cells. Series A compounds differed from those in Series B by having a hydroxypropyl as opposed to an ethyl group linking the imidazole ring and the nitrosoureido function. Four analogues, including the imidazole and the 2-, 4-, and 5-NO2 derivatives, were evaluated in each series. Cells were exposed to the various compounds for 4 h under aerobic and hypoxic conditions, and toxicity was assessed by clonogenic assay. Corresponding analogues in Series A and B were equally toxic to HeLa-MR cells. Preferential hypoxic toxicity was observed only with the 2-NO2 derivative in either series (I-278, Series A; I-282, Series B). For either compound a dose enhancement factor of 2.4 was observed for hypoxic exposures. The Mer+ HeLa-S3 cells were considerably more resistant to the NI-CENU than were their HeLa-MR counterparts. In further contrast to the HeLa-MR data, the Series B compounds were consistently more effective against the HeLa-S3 cells than were their corresponding Series A analogues. The enhanced effectiveness of the Series B compounds in HeLa-S3 cells may be related to the fact that these compounds express carbamoylating activity whereas Series A compounds lack this property. Again only I-278 and I-282 were preferentially toxic to hypoxic cells; however, the aerobic/hypoxic differential was dramatically reduced (dose enhancement factor = 1.3) as compared to that observed with the HeLa-MR cells. The enhanced hypoxic toxicity of the 2-NO2 NI-CENUs was not due to direct hypoxic toxicity of the nitro moiety but presumably is the result of enhancement of CENU toxicity (i.e., chemosensitization). The data suggest that much lower concentrations of NI may be required to observe chemosensitization when the NI and chemotherapeutic agent are administered as a single mixed-function compound.

Aerobiosis↗
PubMed1988

DNA-nitrosourea interactions. High-performance liquid chromatography of cross-linked dinucleosides and substituted deoxynucleosides.

A reconstituted mixture of five cross-linked dinucleosides possibly involved in DNA-nitrosourea interactions, and of their degradation products (nucleobases, deoxynucleosides and mono- or disubstituted deoxynucleosides), was analysed by reversed-phase high-performance liquid chromatography using C18 columns and an diode-array detector. The chromatographic conditions for separating the twenty-one investigated compounds were optimized, and the compounds were identified by both their retention times and their UV spectra. A structure-retention time relationship was observed under suitable conditions and is discussed. Its validity was confirmed by the prediction of the retention time of a new cross-linked dinucleoside synthesized for this purpose.

Chromatography, High Pressure Liquid↗
PubMed1988

On a new class of mixed-function drugs associating nitroimidazoles and CENU: the NICE-NU.

Two series of (2-chloroethyl) nitrosoureas (NICE-NU) bearing a nitroimidazole group have been synthesized for anti-tumor evaluation with the aim of chemopotentiation of their biological activity. Their anti-tumor activity against L1210 in vivo in mice is excellent especially for the series A derivatives where a hydroxy function provides assistance to decomposition. However, the activity of NICE-NU against B16 melanoma is lower.

Animals↗
PubMed1983

Conformational analysis of oligoarabinonucleotides. An NMR and CD study.

A 500 and 300 MHz proton NMR study of the series of oligoarabinonucleotides 5'aAMP, 3'aAMP, aA-aA, (aA-)2aA and (aA-)3aA is presented. In addition, circular dichroism is used to study the stacking behaviour of aA-aA. The complete 1H-NMR spectral assignment of the compounds (except the tetramer) is given. Proton-proton and proton-phosphorus coupling constants, obtained by computer simulation of the high-field region of the spectra, yield information on the conformation of the arabinose rings (N- or S-type) and on the intramolecular stacking properties of the dimer and the trimer. The monomers 5'aAMP and 3'aAMP exhibit a preference for N- and S-type sugar conformation, respectively. It is shown that the dimer aA-aA at low temperature prefers a mixed stacked state of the type aA(S)-aA(N). In the trimer the aA(2)-aA(3) fragment exhibits a conformation similar to that found in the dimer, whereas the aA(1) residue prefers to adopt S-type sugar and has some tendency to stack upon residue aA(2).

Arabinonucleotides↗
PubMedDate not supplied

Synthesis and biological activity of 4-substituted 1-[1-(2-hydroxyethoxy)-methyl-1,2,3-triazol-(4 & 5)-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidines.

The chemical synthesis of some 4-substituted 1-[1-(2-hydroxyethoxy)-methyl-1,2.3-triazol-(4 and 5)-ylmethyl]-1-H-pyrazolo[3,4-d]pyrimidines 12a,b, 13a,b and 14-23 as acyclic nucleosides is described. Treatment of (2-acetoxyethoxy)methylbromide with sodium azide afforded (2-acetoxyethoxy)methylazide 9. The heterocycles 6a,b were alkylated, separately, with propargyl bromide to obtain. regioselectively, 4-(methyl and benzyl)thio-1-(prop-2-ynyl)-1H-pyrazolo[3,4-d]pyrimidines 7a,b. These N-alkylated products were condensed with compound 9 via a 1,3-dipolar cycloaddition reaction to obtain, after separation and deprotection, 1,4- and 1,5-regioisomers 12a,b and 13a,b. The deprotected acyclic nucleosides 12a and 13a served as precursors for the preparation of 4-amino (14 and 15), 4-methylamino (16 and 17). 4-benzylamino (18 and 19), 4-methoxy (20 and 21) and 4-hydroxy (22 and 23) analogues. Compounds 7a,b and all deprotected acyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-(IIIB) and HIV-2(ROD) in MT-4 cells and for their anti-tumor activity. No marked activity was found. However, initial evaluation of 6a,b, 7a,b. 12a,b, 13a,b and 14-23 showed that compound 7b has marked activity against M. tuberculosis.

Anti-HIV Agents↗