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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↗
PubMed1982

Poly(adenylic acids) containing the antibiotic tubercidin -- base pairing and hydrolysis by nuclease S1.

Poly(adenylic acids) containing the antibiotic tubercidin (7-deazaadenosine) form double strands with poly(uridylic acid) by Watson-Crick base pairing. The stability of these complexes is enhanced by an increasing adenosine content of the polymers. Whereas poly(tubercidylic acid) can bind only one poly(U) chain, the copolymers of adenylic and tubercidylic acid bind a second strand of poly(U). The melting temperatures imply a triple strand formation in a similar geometry as found for poly(A).2poly(U). The diminished hypochromicity of those complexes suggests semi-Hoogsteen base pairs, caused by the lack of N-7 in the antibiotic. As found for poly(A).poly(U), the double-stranded poly(Tu).poly(U) is not hydrolyzed by nuclease S1. In contrast to the four regular homopolyribonucleotides the single-stranded poly(Tu) is cleaved very rapidly. This may be due to a great flexibility of the polynucleotide chain. Moreover TuMP does not inhibit the enzymic digestion. Both phenomena imply a mechanism for the antibiotic action of tubercidin on the polymer level.

Base Composition↗
PubMed1980

Halogenation of tubercidin by N-halosuccinimides. A direct route to 5-bromotubercidin, a reversible inhibitor of RNA synthesis in eukaryotic cells.

Tubercidin may be directly brominated by reaction with N-bromosuccinimide in DMF to give 5-bromotubercidin, a reversible inhibitor of RNA synthesis. When buffered with potassium acetate the major product is 6-bromotubercidin. 5,6-Dibromotubercidin is formed in minor amounts under both conditions. N-Chlorosuccinimide and tubercidin give 5-chlorotubercidin and 5,6-dichlorotubercidin.

Bromosuccinimide↗
PubMed1979

5-FU versus combination therapy with tubercidin, streptozotocin, and 5-FU in the treatment of pancreatic carcinomas: COG protocol 7230.

From May 1972 until May 1976, 105 patients were entered on Central Oncology Group protocol 7230 to compare the combination of streptozotocin, tubercidin, and 5-fluorouracil (5-FU) versus 5-FU alone in the treatment of adenocarcinoma and islet cell carcinoma of the pancreas. Twenty-nine were not evaluable. Thirty-six evaluable cases received 5-FU, and 40 received the combination, with no significant difference in time to progression or survival. Toxicity in the two regimens was somewhat different but was essentially similar in magnitude. Results indicate no benefit in the treatment of adenocarcinoma of the pancreas with the three-drug combination over 5-FU alone. All of the islet cell tumor patients benefited from the combination by response or arrest of progression of disease. Further study should be directed toward the use of this combination in the treatment of functioning and non-functioning islet cell tumors of the pancreas.

Adenocarcinoma↗
PubMed1993

Molecular biology studies of tubercidin resistance in Trypanosoma cruzi.

Trypanosomatids are incapable of de novo purine synthesis; purines are obtained through the scavenging of exogenous nucleosides. To advance our understanding of purine utilization, we mutagenized a Trypanosoma cruzi stock and selected for resistance to high levels of tubercidin (7-deazaadenosine, TUB), a purine analog. The TUB-resistant stocks were > 100 times more resistant to TUB than was the parental stock. TUB and uridine transport in the TUB-resistant stocks decreased by 50%-90%, whereas thymidine and adenosine transport were unaffected. These data imply that TUB-resistant stocks have defects in the pathways involved in the transport of TUB and uridine but not in the thymidine and adenosine transport pathways. Karyotype analyses using specific probes showed that the deletion of a 950-kb chromosome-size DNA occurred in both of the TUB-resistant stocks. These data suggest that genes involved in nucleoside transport are located in this DNA region. This study will facilitate the identification and characterization of the specific genes involved in nucleoside transport and aid in the elucidation and development of new chemotherapeutics for Chagas' disease.

Animals↗
PubMed1984

(+/-)-3-(4-Amino-1H-pyrrolo[2,3-d]pyrimidin-1-yl)-5-(hydroxymethyl)- (1 alpha,2 alpha,3 beta,5 beta)-1,2-cyclopentanediol, the carbocyclic analogue of tubercidin.

(+/-)-3-(4-Amino-1H-pyrrolo[2,3-d]pyrimidin-1-yl)-5-(hydroxymethyl)- 1 alpha,2 alpha,3 beta,5 beta)-1,2-cyclopentanediol (9), the carbocyclic analogue of tubercidin, prepared from (+/-)-3-amino-5-(hydroxymethyl)-(1 alpha,2 alpha,3 beta,5 beta)- 1,2-cyclopentanediol (6), is cytotoxic to cells containing adenosine kinase but not to cells that do not, indicating that its activity depends on phosphorylation. Although inactive against P388 leukemia in mice and against herpes and influenza viruses in vitro, it showed marginal activity against respiratory syncytial, vesicular stomatitis, and rhino viruses in vitro.

Animals↗
PubMed2001

Syntheses of puromycin from adenosine and 7-deazapuromycin from tubercidin, and biological comparisons of the 7-aza/deaza pair.

Protection (O5') of 2',3'-anhydroadenosine with tert-butyldiphenylsilyl chloride and epoxide opening with dimethylboron bromide gave the 3'-bromo-3'-deoxy xylo isomer which was treated with benzylisocyanate to give the 2'-O-(N-benzylcarbamoyl) derivative. Ring closure gave the oxazolidinone, and successive deprotection concluded an efficient route to 3'-amino-3'-deoxyadenosine. Analogous treatment of the antibiotic tubercidin [7-deazaadenosine; 4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine] gave 3'-amino-3'-deoxytubercidin. Trifluoroacetylation of the 3'-amino function, elaboration of the heterocyclic amino group into a (1,2,4-triazol-4-yl) ring with N,N'-bis[(dimethylamino)methylene]hydrazine, and nucleophilic aromatic substitution with dimethylamine gave puromycin aminonucleoside [9-(3-amino-3-deoxy-beta-D-ribofuranosyl)-6-(dimethylamino)purine] and its 7-deaza analogue. Aminoacylation [BOC-(4-methoxy-L-phenylalanine)] and deprotection gave puromycin and 7-deazapuromycin. Most reactions gave high yields at or below ambient temperature. Equivalent inhibition of protein biosynthesis in a rabbit reticulocyte system and parallel growth inhibition of several bacteria were observed with the 7-aza/deaza pair. Replacement of N7 in the purine ring of puromycin by "CH" has no apparent effect on biological activity.

Adenosine↗
PubMed2003

Quantitative structure-activity relationship study of 5-iodo- and diaryl-analogues of tubercidin: inhibitors of adenosine kinase.

The adenosine kinase inhibitory (AKI) activity of 5-iodo and diaryl analogues of tubercidin is quantitatively analyzed using Fujita-Ban and Hansch type analyses. The Fujita-Ban analysis being a non-parametric approach assigned the highest contribution to Cl at the X-position, C6H4-4-Cl, C6H5, 2-furanyl and I at the Y-position and CH2NH2 and CH3 at the Z-position. In addition, a OH substituent at the C-position also emerged as a better choice possibly due to its engagement in hydrogen bonding with some active site function. Thus a compound having Cl, C6H4-4-Cl, CH2NH2 and OH respectively at X-, Y-, Z- and C-positions is predicted to have a potency nearly 1.5 orders of magnitude higher than the most potent compound of the parent data set. The Hansch type analysis, on the other hand, is a parametric approach and is carried out on two sub-sets of original compounds. This sub-division is based on size and nature of the substituents present at the X- and Y-positions. For the compounds in the first sub-set the derived significant correlation equation suggested that the substituent at the Y-position exhibiting a higher field effect and a substituent such as Cl and CH2NH2 at X- and Z-positions, respectively, are important for a compound to show increased AKI activity. Thio/alkylthio at X and CH2OCH3 at Z, on the other hand, lead to a detrimental effect. Similarly for the compounds in the second subset, the derived significant correlation equation showed that a substituent at the X-position having a higher negative field effect, a substituent at the Y-position having bulky groups and the C-position occupied by a OH group are essential for enhancement of the activity of a compound.

Adenosine Kinase↗
PubMed1987

Self-association and protonation of adenosine 5'-monophosphate in comparison with its 2'- and 3'-analogues and tubercidin 5'-monophosphate (7-deaza-AMP).

The concentration dependence of the chemical shifts of the protons H-2, H-8 and H-1' for 2'-, 3'- and 5'-AMP2- and of the protons H-2, H-7, H-8 and H-1' for tubercidin 5'-monophosphate (= 7-deaza-AMP2-; TuMP2-) has been measured in D2O at 27 degrees C to elucidate the self-association of the nucleoside monophosphates (NMPs). The results are consistent with the isodesmic model of indefinite non-cooperative stacking; the association constants for all four NMPs are very similar: K approximately 2 M-1. These 1H-NMR measurements and those on the dependence of the chemical shifts on the pD of the solutions indicate that the NMP2- species exist predominately in the anti conformation. Comparison of the shift data for 5'-TuMP and 5'-AMP shows that no hydrogen bonding between N-7 and -PO3H- occurs; hence, the previously observed and confirmed 'wrongway' chemical shift [Martin, R. B. (1985) Acc. Chem. Res 18, 32] connected with the deprotonation of the -PO3H- group most probably results from the anisotropic properties of the phosphate group which is in the anti conformation close to N-7. From the dependence between the chemical shift and the pD of the solutions the acidity constants were calculated for the four protonated NMPs, and for adenosine and D-ribose 5'-monophosphate. The measurements also allow an estimation of the first acidity constant of H3(5'-AMP)+ (pKDD3(AMP) = 0.9 and pKHH3(AMP) = 0.4). The values for pKHH2(NMP) and pKHH(NMP) were also determined from potentiometric pH titrations in aqueous solution (I = 0.1 M, NaNO3; 25 degrees C). The agreement of the results obtained by the two methods is excellent. The position of the phosphate group at the ribose moiety and the presence of N-7 in the base moiety influence somewhat the acid-base properties of the mentioned NMPs. Measurements with 5'-AMP in 50% (v/v) aqueous dioxane show that lowering of the solvent polarity facilitates removal of the proton from the H+(N-1) site while the -PO2-3 group becomes more basic; this increases the pH range in which the monoprotonated H(5'-AMP)- species is stable and which is now also extended into the physiological pH region. Some consequences of this observation for biological systems are indicated.

Adenine Nucleotides↗
PubMed1975

Treatment of schistosomiasis mansoni and japonica in baboons with tubercidin given by direct intravenous injection.

Baboons (Papio cyanocephalus and P. anubis), infected with Schistosoma mansoni or S. japonicum, were treated with single doses of tubercidin (7-deazaadenosine; Tu), 1, 3, and 5 mg per kg of body weight, administered by intravenous drip. Crystalline Tu was dissolved in sterile 0.9% NaCl solution (1 mg per ml), and the solution was delivered at a rate of 4 ml per minute. Detectable short-term host toxicity was limited to the 5 mg per kg dose, mainly in the form of reversible mild to moderate kidney damage. Only this 5 mg per kg dose administered to baboons with relatively heavy S. mansoni infections was capable of completely suppressing fecal egg excretion for 6 to 8 weeks, eliminating the female worms, and terminating active disease, as indicated by histopathological findings. Comparable effects were achieved following the administration of the 3 mg per kg dose to baboons with moderate to heavy S. japonicum infections.

Animals↗
PubMed1976

Activity of tubercidin against immature Fasciola hepatica in mice.

HaM/ICR females mice (20 to 25 g), infected with from 3 to 5 Fasciola hepatica metacercariae per os, were treated with a single dose of thepurine nucleoside analog tubercidin (7-deaza-adenosine; Tu) 7, 14, 21, and 28 days postexposure.Tu was administered either by direct intravenous injection or intraerythrocytically. Most of the flukes were killed and host survival rates were markedly increased if treatment was started within 3 weeks postexposure. The minimal single intravenous dose of Tu that was maximally effective was between 10 and 20 mg/kg.

Animals↗
PubMed1982

Effect of nitrobenzylthioinosinate on the toxicity of tubercidin and ethidium against Trypanosoma gambiense.

The coadministration of tubercidin and ethidium to mice infected with Trypanosoma gambiense gave a better parasite clearance than either of the single drugs. The combination was also more toxic to the mice but the inclusion of nitrobenzylthioinosinate in the therapy significantly alleviated the toxicity of the drug combination. Nitrobenzylthioinosinate per se had no trypanocidal activity and did not affect the trypanocidal action of the drugs. The biochemical basis for the nitrobenzylthioinosinate action appears to be due to the reduction of access of the drugs to tissues or organs sensitive to the toxic drugs. The potential for the use of this compound with nucleoside analogue compounds in the therapy of African trypanosomiasis is suggested.

Animals↗
PubMed1975

Long-term efficacy of tubercidin against schistosomiasis japonica and mansoni in primates.

Schistosomiasis japonica in capuchin msnkeys (Cebus apella) and schistosomiasis mansoni in baboons (Papio cyanocephalus and P. hamadryas) were completely arrested for 6 months in every infected primate receiving a single treatment with tubercidin (Tu), administered after prior absorption into 20% of their red cells. It is very likely that a single treatment with Tu sequestered in only 15% of the hosts' red cells would also be 100% effective for prolonged periods of time, but that with lower doses some relapses would be expected. Babbons with patent Schistosoma mansoni infections were rechallenged with S. mansoni cercariae 4 months after treatment with Tu. Although Tu eliminated almost all the sexually mature female worms from the primary infection but spared most of the males for continuing sojourn within their hosts, the baboons retained their full susceptibility to reinfection, as indicated by worm burdens and fecal egg excretion. However, the granulomatous reaction in the rechallenged Tu-treated baboons to new masses of eggs trapped in their livers appeared to be less intense than was seen in animals with primary infections.

Animals↗
PubMed1998

Purification and characterization of GTP cyclohydrolase I from Streptomyces tubercidicus, a producer of tubercidin.

GTP cyclohydrolase I catalyzing the first reaction in the biosynthesis of pterin moiety of folic acid in bacteria, was purified from Streptomyces tubercidicus by at least 203-fold with a yield of 32% to apparent homogeneity, using ammonium sulfate fractionation, DEAE-cellulose, Sepharose CL-6B, and hydroxylapatite column chromatography. The molecular weight of the native enzyme was estimated to be 230,000 daltons by gel permeation chromatography. The purified enzyme gave a single band on sodium dodesyl sulfate-polyacrylamide gel electrophoresis and its molecular weight was apparently 58,000 daltons. These results indicate that the enzyme consists of four subunits with the same molecular weight. The K(m) and Vmax values for GTP of the purified enzyme were determined to be 80 microM and 90 nmol/min (mg protein), respectively. The optimum pH and temperature for the enzyme reaction were pH 7.5-8.5 and 40-42 degrees C, respectively. Coenzyme or metal ion was not required for the enzyme activity. The enzyme activity was inhibited by most divalent cations, while it was slightly activated by potassium ion. In case of nucleotides, CTP, GMP, GDP, and UTP inhibited enzyme activity, among which GDP exhibited the strongest inhibitory effect.

Anti-Bacterial Agents↗