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At least 109 records · Page 6Linked to original sources
PubMed1986

Synthesis and antitumor activity of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin prepared via ring closure of a 1,2,4-triazine precursor.

Several 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin were prepared and tested for their antitumor activity in cell culture. Dehydrative coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one (5) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6a) and further ring closure of the reaction product (7) provided 6-amino-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (8). Condensation of 5 with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid chloride (6b), followed by ring annulation, also gave 8 in good yield. Debenzoylation of 8 furnished the guanosine analogue 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)-one (4b). Thiation of 8 with P2S5, followed by debenzoylation of the thiated product (11a), afforded 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)- thione (11b). Methylation of the sodium salt of 11a gave the 8-methylthio derivative (10), which on ammonolysis furnished 6,8-diamino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazine (9). Diazotization of 10 with tert-butyl nitrite (TBN) and SbCl3 in 1,2-dichloroethane gave the corresponding 6-chloro derivative (12a). Reaction of 10 with TBN in THF in the absence of a halogen source gave 8-(methylthio)-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4- triazolo[3,4-f]-1,2,4-triazine (12b). Ammonolysis of 12b gave the azaformycin A analogue 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[3,4-f]-1,2,4-triazine (3), which on deamination afforded 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (4a). The azaformycin A analogue (3) showed pronounced inhibitory effects against L1210, WIL2, and CCRF-CEM cell lines with ID50 values ranging from 5.0 to 7.3 microM.

Antibiotics, Antineoplastic↗
PubMed1984

Biological activity and a modified synthesis of 8-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-a]pyrazine, an isomer of formycin.

A two-step synthesis of 8-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-a]pyrazine (3), which is an isomer of formycin that resembles 3-deazaadenosine, is reported. Compound 3 is also described as as being a very poor substrate for adenosine deaminase and to be both a competitive and an irreversible inhibitor of S-adenosylhomocysteinase in the synthesis direction. L1210 cell growth in culture was inhibited by 3. Compound 3 was not converted to the nucleotide level in erythrocytes but was found to inhibit both the cellular uptake of nucleic acid precursors and their incorporation into the nucleic acids of L1210 cells. Finally, 3 was found to be a weak antiviral agent and coronary vasodilator.

Adenosine Deaminase↗
PubMed1986

Synthesis of 5-chloroformycin A, 5-chloro-2'-deoxyformycin A and certain related 5,7-disubstituted 3-beta-D-ribofuranosylpyrazolo[4,3-d] pyrimidines from formycin A.

A facile synthesis of 7-amino-5-chloro-3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine (5-chloroformycin A, 6), 7-amino-5-chloro-3-(2-deoxy-beta-D-erythro-pentofuranosyl) pyrazolo [4,3-d]-pyrimidine (5-chloro-2'-deoxyformycin A, 13) and certain related 5,7-disubstituted pyrazolo[4,3-d]pyrimidine ribonucleosides is described starting with formycin A. Thiation of tri-O-acetyloxoformycin B (4b) with phosphorus pentasulfide, followed 3-beta-D-ribofuranosyl-7-thioxopyrazolo[4,3-d] pyrimidin-5(1H,4H,6H)-one (3b) in excellent yield. Chlorination of 4b with either phosphorus oxychloride or phenyl phosphonicdichloride furnished the key intermediate 5,7-dichloro-3-(2,3, 5-tri-O-acetyl-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (5a), which on deacetylation afforded 5,7-dichloro-3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine (5b). Ammonolysis of 5a with liquid ammonia gave 6, whereas with MeOH/NH3, a mixture of 6 and 7-methoxy-5-chloro-3-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (7) was obtained. Reaction of 6 with lithium azide and subsequent hydrogenation afforded 5-aminoformycin A (10). Treatment of 5a with thiourea gave 5-chloro-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) pyrazolo[4,3-d]pyrimidine-7(1H,6H)-thione (8a), which on further reaction with sodium hydrosulfide furnished 3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine-5,7(1H,4H,6H)-dithione (11). The four-step deoxygenation procedure using phenoxythiocarbonylation of the 2'-hydroxy group of the 3', 5'-protected 6 gave 5-chloro-2'-deoxyformycin A (13).

Antibiotics, Antineoplastic↗
PubMed1975

Polynucleotides. XXXI1. Synthesis of AUG analogs containing 8,2'-S-cycloadenosine, 8,5'-S-cycloadenosine, 8-bromoadenosin, 8-oxyadenosine and formycin in the first position of the codon.

Five AUG analogs having 8,2'-S-cycloadenosine (I), 8,5'-S-cycloadenosine (II), 8-bromoadenosine (III), 8-oxyadenosine (IV) and formycin (V) in the first position of ApUpG W were synthesized. 3'-Phosphates of I, II and V were synthesized by phosphorylation using cyanoethylphosphate and DCC. In the case of II, 2', 3'-cyclic phosphate was directly obtained. 3'-Phosphates, thus obtained, were properly protected on the 2'-OH and/or the N6-amino group and condensed with U(OBz)pGiBu(iBu)2 using DCC to give ApUpG analogs. Some properties on paper chromatography and electrophoresis, and the UV and CD spectra of these trinucleoside diphosphates are reported.

Adenine Nucleotides↗
PubMed1992

Experimental chemotherapy of leishmaniasis with adenosine analogue Formycin A, in combination with inhibitor of nucleoside transport, nitrobenzylthioinosinate.

A single dose of the adenosine analogue Formycin A (FoA) (20 mg/kg), combined with nitrobenzyl mercaptopurine ribonucleoside 5'-monophosphate (NBMPR-P) (10 mg/kg), a prodrug of nitrobenzylthioinosine (NBMPR), was effective in reducing the size of the foot pad lesions from 7.4 +/- 0.2 to 3.9 +/- 0.2 of Syrian golden hamsters infected with Leishmania major. There was a statistical difference (p < 0.01) in the size of the foot pad by the fifth day between the infected groups that received treatment and the controls, as well as between the groups that were treated with combined drugs and FoA only. The initial reduction in size of the foot pad noted in the group that received only FoA was transient. The effect of FoA or FoA combined with NBMPR on the in vitro cultured promastigotes was similar, indicating that the transport inhibitor might be manipulating the availability of FoA in the host's macrophages where the leishmania amastigotes are resident. The results further indicate the need to explore the usefulness of combining cytotoxic nucleoside analogues with host protecting nucleoside transport inhibitors in the treatment of protozoan parasitic infections.

Animals↗
PubMed1985

Formycin 3' end modified tRNATrp. Recognition by avian myeloblastosis virus reverse transcriptase and primer function.

Primer tRNATrp has been modified at the 3' end by adenosine analogues: 2'deoxyadenosine, 3'deoxyadenosine, 3' amino-3' deoxyadenosine and formycin. Aminoacylation of modified tRNATrp with cognate aminoacyl-tRNA synthetase and primer function for DNA synthesis catalyzed by AMV reverse transcriptase have been studied. The tRNATrp was able to accept tryptophan but did not initiate the DNA synthesis directed by 35S AMV RNA. Recognition of modified tRNATrp by AMV reverse transcriptase was not affected as followed by enzyme-tRNA complex formation. The functional consequences of these effects are discussed.

Adenosine↗
PubMed1987

Study of the nucleotide binding site of the yeast Schizosaccharomyces pombe plasma membrane H+-ATPase using formycin triphosphate-terbium complex.

The plasma membrane of yeasts contains an H+-ATPase similar to the other cation transport ATPases of eukaryotic organisms. This enzyme has been purified and shows H+ transport in reconstituted vesicles. In the presence of Mg2+, formycin triphosphate (FTP) is hydrolyzed by the H+-ATPase and supports H+ transport. When combined with terbium ion, FTP (Tb-FTP) and ATP (Tb-ATP) are no longer hydrolyzed. Competition between Mg-ATP and Tb-FTP for ATP hydrolysis indicates that terbium-associated nucleotides bind to the catalytic site of the H+-ATPase. The fluorescent properties of the Tb-FTP complex were used to study the active site of the H+-ATPase. Fluorescence of Tb-FTP is greatly enhanced upon binding into the nucleotide site of H+-ATPase with a dissociation constant of 1 microM. Tb-ATP, Tb-ADP, and Tb-ITP are competitive inhibitors of Tb-FTP binding with Ki = 4.5, 5.0, and 6.0 microM, respectively. Binding of Tb-FTP is observed only in the presence of an excess of Tb3+ with an activation constant Ka = 25 microM for Tb3+. Analysis of the data reveals that the sites for Tb-FTP and Tb3+ binding are independent entities. In standard conditions these sites would be occupied by Mg-ATP and Mg2+, respectively. These findings suggest an important regulatory role of divalent cations on the activity of H+-ATPase. Replacement of H2O by D2O in the medium suggests the existence of two types of nucleotide binding sites differing by the hydration state of the Tb3+ ion in the bound Tb-FTP complex.

Adenosine Triphosphate↗
PubMed1989

The anti-conformation of 2',3'-dideoxy nucleosides may be essential for anti-HIV activity: evidence from the crystal structure of 2',3'-dideoxy formycin A.

The crystal structure of the nucleoside 2',3'-dideoxyformycin A has been determined. The structure shows a syn conformation about the glycosidic bond, stabilised by an intramolecular hydrogen bond between the 05' and N3 atoms. HIV activity was examined in a syncytium inhibition assay. In contrast to the marked decrease in viral titre observed with 2',3'-dideoxycytidine, the formycin analogue produced no effect. It may be concluded that the syn conformation for a dideoxy nucleoside is probably deleterious to HIV inhibition of HIV replication.

Antiviral Agents↗