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PubMed1987

Nucleic acid related compounds. 51. Synthesis and biological properties of sugar-modified analogues of the nucleoside antibiotics tubercidin, toyocamycin, sangivamycin, and formycin.

Treatment of 7-amino-3-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (formycin) with alpha-acetoxyisobutyryl bromide followed by deprotection of the resulting trans-vicinal acetoxy bromides and hydrogenolysis of the separated bromohydrins gave 2'-deoxy-(23%) and 3'-deoxyformycin (32%) after complete deprotection and purification of their hydrochloride salts. An analogous sequence gave 3'-deoxytoyocamycin and/or 3'-deoxysangivamycin in approximately 80% yields from toyocamycin. Antiviral, antineoplastic, and antimetabolic effects were evaluated for the formycin compounds and 4-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine (tubercidin), its 5-cyano- (toyocamycin), and 5-carbamoyl-(sangivamycin) antibiotic congeners in comparison with their 2'-deoxy, 3'-deoxy, and arabino analogues. In all cases, the modified-sugar compounds were less cytotoxic than the parent antibiotics. The majority also exhibited lower antiviral potency. However, the xylo-tubercidin analogue retained potent antiherpes 1 and 2 activity with decreased cytotoxicity. Labeled metabolite studies suggested that effects of these compounds on RNA and/or protein synthesis might be more significant than interference with DNA synthesis.

Animals↗
PubMed1989

Evidence of a calcium-induced structural change in the ATP-binding site of the sarcoplasmic-reticulum Ca2+-ATPase using terbium formycin triphosphate as an analogue of Mg-ATP.

Terbium ions and terbium formycin triphosphate have been used to investigate the interactions between the cation and nucleotide binding sites of the sarcoplasmic reticulum Ca2+-ATPase. Three classes of Tb3+-binding sites have been found: a first class of low-affinity (Kd = 10 microM) corresponds to magnesium binding sites, located near a tryptophan residue of the protein; a second class of much higher affinity (less than 0.1 microM) corresponds to the calcium transport sites, their occupancy by terbium induces the E1 to E2 conformational change of the Ca2+-ATPase; a third class of sites is revealed by following the fluorescence transfer from formycin triphosphate (FTP) to terbium, evidencing that terbium ions can also bind into the nucleotide binding site at the same time as FTP. Substitution of H2O by D2O shows that Tb-FTP binding to the enzyme nucleotide site is associated with an important dehydration of the terbium ions associated with FTP. Two terbium ions, at least, bind to the Ca2+-ATPase in the close vicinity of FTP when this nucleotide is bound to the ATPase nucleotide site. Addition of calcium quenches the fluorescence signal of the terbium-FTP complex bound to the enzyme. Calcium concentration dependence shows that this effect is associated with the replacement of terbium by calcium in the transport sites, inducing the E2----E1 transconformation when calcium is bound. One interpretation of this fluorescence quenching is that the E1----E2 transition induces an important structural change in the nucleotide site. Another interpretation is that the high-affinity calcium sites are located very close to the Tb-FTP complex bound to the nucleotide site.

Adenosine Triphosphate↗
PubMedDate not supplied

Sensitive fluorimetric assay for adenosine deaminase with formycin as substrate; and substrate and inhibitor properties of some pyrazolopyrimidine and related analogues.

The nucleoside antibiotic formycin, 7-amino-3-(beta-D-ribofuranosyl)pyrazolo(4,3-d)pyrimidine, a structural analogue of adenosine, is deaminated about 10-fold faster by adenosine deaminase than adenosine itself, and is therefore a superior substrate for both routine assays and kinetic studies with the purified enzyme. The luminescence properties of formycin have been profited from to develop a fluorimetric assay for adenosine deaminase which is considerably more sensitive than the spectrophotometric procedure widely employed with adenosine as substrate. Examples are presented of its application to routine assays of adenosine deaminase levels in cellular extracts, as well as to kinetic studies with the purified enzyme, including the properties of some pyrazolopyrimidine and purine substrates and inhibitors.

Adenosine Deaminase↗
PubMedDate not supplied

Properties of 5'-AMP deaminase and its inhibitors with the aid of a continuous fluorimetric assay with formycin-5'-phosphate as substrate.

A new continuous fluorimetric assay for AMP deaminase activity is described. The method makes use of a fluorescent analog of 5'-AMP, formycin-5'-phosphate (5'-FMP), which undergoes deamination to formycin B-5'-phosphate, not fluorescent at neutral pH. The pH-dependence for deamination of 5'-FMP is similar to that for 5'-AMP, but shifted about 0.2 units to more acidic pH. Deamination of 5'-FMP may also be followed spectrophotometrically at 306 nm, permitting better assays of crude extracts. Some kinetic results obtained by means of the new method for AMP deaminase from chick and rabbit skeletal muscle are presented. In particular it was found that the natural product of deamination, 5'-IMP exhibited allosteric inhibition of the chick enzyme with Ki values 1.6 mM, 1.2 mM and 1.0 mM at pH 5.8, 6.5 and 7.3, respectively. Activation by diadenosine tetraphosphate, Ap4A, reported for mouse muscle AMP deaminase, has not been noted for the chick enzyme. Inhibition by the transition state analogs, coformycin and 2'-deoxycoformycin, was observed for both rabbit and chick deaminases with Ki values approximately 1 microM and approximately 1.6 microM respectively. Kinetic data for coformycin-5'-phosphate show it to be a tight-binding inhibitor with Ki less than 0.6 x 10(-9) M as compared to 1 x 10(-9) M for 2'-deoxycoformycin-5'-phosphate.

AMP Deaminase↗
PubMed1978

Cyclic phosphates of formycin.

The syntheses of N1- and N2-isopropylformycin (10, 11), formycin 3',5'-cyclic and 2',3'-cyclic phosphate (3,7) and their N-methyl and N-isopropyl derivatives (13, 15, 19, 23) are described. It was observed that substitution at N1 or N2 with a bulky alkyl group or cyclic phosphorylation of the ribose moiety made formycin resistant to adenosine deaminase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Thin-layer chromatographic analysis of fludarabine and formycin A in human plasma.

Fludarabine and formycin A, extracted from plasma, were separated by TLC method on silica gel and aluminium oxide by horizontal development, using suitable mobile phases. The substances were visualized by UV irradiation. After extraction from plasma it was possible to detect 100 ng of fludarabine and 200 ng of formycin A. These results suggested that the TLC system is useful for the initial detection and identification of these drugs in emergencies.

Antineoplastic Agents↗
PubMed1980

Analogues of formycins A and B: synthesis and some properties of methyl derivatives of 7-amino and 7-keto pyrazolo(4,3-d)pyrimidines.

Starting from the synthesis of 3-propyl-7-ketopyrazolo(4,3-d)pyrimidine (a formal analogue of formycin B), this was converted to the 7-thio derivative, which was aminated to give 3-propyl-7-aminopyrazolo(4,3-d(pyrimidine (a formal analogue of formycin A) and its methylamino derivatives. With the aid of different methylating agents, all four possible ring N-mono-methyl derivatives of the foregoing have been synthesized. Dimethyl derivatives were prepared on a small scale and identified by cross-methylation reactions, spectral properties and chromatographic behaviour. The basic physico-chemical properties of all the foregoing are described, including ultraviolet absorption spectra, spectrophotometrically determined pK values, and the 1H chemical shifts in aqueous medium and/or dimthjyl sulphoxide. The spectral properties of the various analogues indicate that the N6-methyl derivatives exist predominantly in the imino form, in contrast to the predominant amino form of the corresponding analogue from the adenine series, N1-methyladenine, but similar to the fixed imino form of N1-methyl-9-substituted adenines.

Amination↗
PubMed1977

Preparation and properties of formycin analogues methylated on the pyrazolo ring nitrogens and/or the ribose cis-hydroxyls.

1. Diazomethane treatment of formycin A in the presence or absence of SnCl2 as catalyst, was used for the preparation of the 2'-O-methyl, 3'-O-methyl, N1-methyl and N2-methyl derivatives. The four possible dimethylated derivatives, 2'(3")-O,N1(N2)-dimethylformycins, were obtained by controlled treatment of formycin with diazomethane in the presence of SnCl2, and subsequent column chromatography for product isolation. 2. All the foregoing products were characterized and identified by chromatography, ultraviolet absorption spectra, and proton magnetic resonance spectroscopy. Extensive u.v. spectral data, and spectrally determined pK values, for the various derivatives are presented. 3. N2-Methylformycin B was also prepared by enzymatic deamination of the parent N2-methylformycin A. 4. The sequence of elution of N1-methylformycin and N2-methylformycin on a strongly basic ion exchange column suggested that the latter is in the syn conformation. The susceptibility of N2-methylformycin to adenosine deaminase shows that this analogue may adopt the anti conformation on reaction with the enzyme. 5. The active species in the SnCl2-catalysed monomethylation of the 2'(3') cishydroxyls of ribonucleosides by diazomethane was shown to be an organo-tin product of the reaction of SnC2 with diazomethane. This product, not identified, contained no nitrogen or chlorine. 6. A simple column chromatographic procedure is described for the desalting of heterocyclic bases and their nucleosides with pK values for ring protonation down to about 0.

Antibiotics, Antineoplastic↗
PubMed1995

Simulation analysis of formycin 5'-monophosphate analog substrates in the ricin A-chain active site.

Ricin is an RNA N-glycosidase that hydrolyzes a single adenine base from a conserved loop of 28S ribosomal RNA, thus inactivating protein synthesis. Molecular-dynamics simulation methods are used to analyze the structural interactions and thermodynamics that govern the binding of formycin 5'-monophosphate (FMP) and several of its analogs to the active site of ricin A-chain. Simulations are carried out initiated from the X-ray crystal structure of the ricin-FMP complex with the ligand modeled as a dianion, monoanion and zwitterion. Relative changes in binding free energies are estimated for FMP analogs constructed from amino substitutions at the 2- and 2'-positions, and from hydroxyl substitution at the 2'-position.

Binding Sites↗
PubMed2003

Identification of the tautomeric form of formycin A in its complex with Escherichia coli purine nucleoside phosphorylase based on the effect of enzyme-ligand binding on fluorescence and phosphorescence.

Fluorescence and phosphorescence emission spectroscopy were employed to study the interaction of Escherichia coli purine nucleoside phosphorylase (PNP) with its specific inhibitor, formycin A (FA), a close structural analogue of adenosine (natural substrate), in the absence and presence of phosphate (P(i), substrate). Formation of enzyme-FA complexes led to marked quenching of enzyme tyrosine intrinsic fluorescence and phosphorescence, with concomitant increases in fluorescence and phosphorescence of FA. Fluorescence resonance energy transfer from the protein Tyr160 residue to the FA base moiety was identified as a major mechanism of protein fluorescence quenching, increased by addition of P(i). The effects of enzyme-FA interactions on the nucleoside excitation and emission spectra for fluorescence and phosphorescence revealed shifts in the tautomeric equilibrium of the bound FA, i.e. from the N(1)-H tautomer (predominant in solution) to the N(2)-H form, enhanced by the presence of P(i). The latter was confirmed by enzyme-ligand dissociation constant ( K(d)) values of 5.9+/-0.4 and 2.1+/-0.3 microM in the absence and presence of P(i), respectively. Addition of glycerol (80%, v/v) led to a lower enzyme affinity ( K(d) approximately 70 microM), without changes in binding stoichiometry. Enzyme-FA complex formation led to a higher increase of the fluorescence than the phosphorescence band of the ligand, consistent with the fact that the N(2)-H tautomer is characterized by a weaker phosphorescence than the N(1)-H tautomeric form. These results show, for the first time, the application of phosphorescence spectroscopy to the identification of the tautomeric form of the inhibitor bound by the enzyme.

Algorithms↗
PubMed1984

Interaction of formycin A-5'-triphosphate with pyruvate carboxylase.

Formycin triphosphate (FTP), a fluorescent analogue of ATP, is a competitive inhibitor of chicken liver pyruvate carboxylase with respect to ATP. The chicken liver enzyme is unable to utilise FTP as a substrate at a measureable rate, but FTP is a poor substrate for the sheep liver enzyme. When FTP binds to the enzyme, its fluorescence is enhanced and in this way the formation of enzyme-FTP complexes can be monitored. Using this property of FTP, the effect of Mg2+ and acetyl-CoA on the binding of nucleoside triphosphates to the chicken liver enzyme was examined. Mg2+ was found to enhance the binding of FTP whilst acetyl-CoA reduced the fluorescence intensity of a mixture of Mg2+, enzyme and FTP. Most probably, this was caused by a conformational change in the enzyme which changed the environment of the fluorophore.

Animals↗
PubMed1990

Guanosine and formycin triphosphates bind at non-catalytic nucleotide binding sites of CF1 ATPase and inhibit ATP hydrolysis.

Guanosine triphosphate and formycin triphosphate (FTP) in the presence of excess Mg2+ can bind to empty non-catalytic sites of spinach chloroplast ATPase (CF1). This results in a greatly reduced capacity for ATP hydrolysis compared to the enzyme with non-catalytic sites filled with ATP. With two GTP bound at non-catalytic sites the inhibition is about 90%; with two FTP bound about 80% inhibition is obtained. Binding and release of the nucleotides from the non-catalytic sites are relatively slow processes. Exposure of CF1 with one or two empty non-catalytic sites to 5-10 microM FTP or GTP for 15 min suffices for about 50% of the maximum inhibition. Reactivation of CF1 after exposure to higher FTP or GTP concentrations requires long exposure to 2 microM EDTA. The findings show that, contrary to previous assumptions, GTP can bind tightly to non-catalytic sites of CF1. They suggest that the presence of adenine nucleotides at non-catalytic sites might be essential for high catalytic capacity of the F1 ATPases.

Adenosine Diphosphate↗
PubMed1985

Anti-leishmanial effect of allopurinol ribonucleoside and the related compounds, allopurinol, thiopurinol, thiopurinol ribonucleoside, and of formycin B, sinefungin and the lepidine WR6026.

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Adenosine↗
PubMed1992

Formycin triphosphate as a probe for the ATP binding site involved in the activation of guanylate cyclase.

Formycin A triphosphate (FTP), a fluorescent analog of ATP, slightly increased basal guanylate cyclase activity, but significantly potentiated guanylate cyclase activity stimulated by atrial natriuretic factor (ANF) in rat lung membranes. FTP potentiated ANF-stimulated guanylate cyclase activity with an EC50 at about 90 microM and inhibited ATP-stimulated guanylate cyclase activity with an IC50 at about 100 microM. These results indicate that FTP binds more tightly than ATP for the same binding site. Therefore, FTP would be an excellent tool for studying the ATP binding site.

Adenosine Triphosphate↗
PubMed1987

American Leishmania spp: formycin B treatment of cutaneous leishmaniasis in mice.

Using foot-pad infection of female C57BL/6, DBA/2J and NMRI-IVIC mice as an animal model for American cutaneous leishmaniasis (ACL), we evaluated the inhibitory effect of Formycin B (FoB) on the infection produced by 7 different Leishmania isolates. When treatment was initiated some days, or even some weeks, after infection a significant leishmanistatic effect was detected on mice infected with all Leishmania isolates, which reached 30-55 weeks for some isolates. The optimal dose schedule was 1.25 mg/kg body weight/day, injected intraperitoneally for 20 consecutive days. Significant differences in the sensitivity of various Leishmania spp. to FoB were found, either in vivo, or in vitro where a high [3H]FoB incorporation rate was found only for certain Leishmania isolates. The low toxicity of this drug and the sensitivity of the 7 Leishmania isolates tested suggest that FoB could be useful in the treatment of ACL.

Animals↗
PubMed1988

Crystal structure of formycin 5'-phosphate: an explanation for its tight binding to AMP nucleosidase.

Formycin 5'-monophosphate (FMP) is a strong competitive inhibitor of AMP nucleosidase with Km/Kis from 1200 to 2600 depending on the source of the enzyme. The crystal structure of FMP has been determined in order to understand the basis for its high affinity for AMP nucleosidases and other biological properties. The key structural features of FMP are (1) the base is the N(7)-H tautomer, (2) the N(3) of the base forms an intramolecular hydrogen bond to the phosphate oxygen O(1), (3) the glycosyl torsion angle is syn with O(4')-C(1') relative to C(9)-C(4) being -6.43 degrees, and (4) the furanose ring pucker is C(3')-endo, with a pseudorotation angle of 20.3 degrees. The major difference between the AMP and FMP structures is that the glycosyl torsion angles differ by 190 degrees. The computed conformational energy necessary to distort AMP so that it has the same glycosyl torsion angle as FMP is 4.6 kcal/mol. This corresponds to a 2100-fold difference in binding energy, in good agreement with the observed interaction between AMP nucleosidase and FMP.

Antibiotics, Antineoplastic↗
PubMed1975

Hybridization of polymers of antibiotic C-nucleoside phosphates, poly(formycin phosphate) and poly(laurusin phosphate)

The ability of complex formation of poly-(formycin phosphate), poly(F), and poly(laurusin phosphate), poly(L), with the polymers of natural polynucleotides was examined mainly by mixing experiments in 0.1 M NaCl-0.05 M sodium cascodylate buffer (pH 7.0) at 2 degrees. Poly(F) formed complexes with poly(U) and poly(I) in the ratio of 1:1 and 1:2, respectively. Poly(L) formed complexes with poly(A) in 2:1 ration and poly(C) in 1:2 and 2:1 ratios in addition to a self-complex. Poly(F) and poly(L) also formed a 1:2 complex between them. Some of these complexes were assumed to contain novel types of base pairings using the 7-NH group. Thus it was concluded that poly(L) could form complexes with both, the oligomer of cycloadenylic acid (øcn-120 degrees) and polymers of natural nucleotides (øcn0degrees), showing flexibility of the torsion angle of the laurusin residue.

Adenosine Monophosphate↗
PubMed1993

Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase.

In an effort to develop potent human purine nucleoside phosphorylase (PNP) inhibitors as immunosuppressive and chemotherapeutic agents, several 8-aminoguanine derivatives were synthesized and evaluated as potential PNP inhibitors. These studies were designed to investigate the hydrophobic effect of a substituent on the N-9 of the purine heterocycle and/or the C-5' positions. Compounds such as 8-aminoguanosine, guanosine, formycin B, and 8-aminoacyclovir containing a p-(fluorosulfonyl)benzoyl moiety were synthesized. The affinity of these compounds to erythrocytic PNP was determined and none of these compounds showed a better affinity than those of the parent compounds. However, we found that the effect of hydrophobicity at the N-9 and the C-5' positions might play an important role in binding to the active site of PNP. Thus, 8-amino-5'-deoxy-5'-(phenylthio)guanosine (19) was found to be the best inhibitor in this series of compounds with a Ki = 0.45 microM.

Binding Sites↗