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PubMed1990

Conformations of deoxydinucleoside phosphates containing pyrimidine-pyrimidine photodimers.

Conformational analysis of deoxydinucleoside monophosphates with the sequences TpT and CpC have been carried out with the incorporation of both cyclobutane type pyrimidine dimers and 6-4 photoadducts using the methods of molecular mechanics energy minimization. The effect of flexibility with respect to sugar geometries and glycosidic torsions have been studied and the relative energies of a large variety of structures have been compared. The salient features obtained from these calculations have been compared with the crystallographic and spectroscopic data on pyrimidine dimer incorporated deoxydinucleoside monophosphates. Effects of "inserting" the energetically favourable conformations of such structures into B-DNA helices have been discussed in terms of the distortions in helical structures.

Cytidine↗
PubMed1995

Induction of cyclobutane pyrimidine dimers, pyrimidine(6-4)pyrimidone photoproducts, and Dewar valence isomers by natural sunlight in normal human mononuclear cells.

Immunocytochemistry was used for the direct measurement of cyclobutane pyrimidine dimers, (6-4) photoproducts, and Dewar isomers in normal human mononuclear cells following irradiation by natural sunlight or by a FS20 broad spectrum UVB sunlamp. The induction of each type of photoproduct was detected following 30-60 min sunlight exposure or with FS20 fluences as low as 50-100 Jm-2. With increasing FS20 fluences, there was a dose-dependent increase in the binding of pyrimidine dimer, (6-4) photoproduct, and Dewar isomer-specific monoclonal antibodies. The relative ratio of Dewar isomer to (6-4) photoproduct antibody binding sites was much higher following exposure to natural sunlight than to broad spectrum UVB. With the (6-4) monoclonal antibody, a small increase in binding sites was evident after a 1-h exposure to natural sunlight. This remained relatively constant with further exposure. These results are consistent with the hypothesis that, following irradiation with natural sunlight, the majority of (6-4) photoproducts are converted into Dewar valence isomers.

Antibodies, Monoclonal↗
PubMed1994

Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells.

Irradiation of cells with short wave ultraviolet light (UV-C) induces both cyclobutane pyrimidine dimers (CPD) as well as pyrimidine 6-4 pyrimidone photoproducts (6-4 PP). We have focused on the removal of both types of DNA photolesions from the transcriptionally active adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT) genes and the inactive c-mos gene. Induction levels of both CPD and 6-4 PP were similar for all three genes analyzed, with the induction of 6-4 PP being about 3-fold lower than of CPD. Repair of CPD was analyzed using the CPD-specific enzyme T4 endonuclease V; repair of 6-4 PP was examined employing Escherichia coli UvrABC excinuclease. Unlike the HPRT gene, in which CPD were removed selectively from the transcribed strand, both strands of the 16-kilobase fragment encompassing the 2.6-kilobase APRT gene were repaired efficiently. This suggests the existence of multiple transcription units in the APRT region including transcription units running in the opposite direction of the APRT gene. Only a marginal part of the CPD was removed from the inactive c-mos gene after 24 h. In all three genes investigated, 6-4 PP were repaired more rapidly than CPD and, as demonstrated for the HPRT and APRT genes, without strand specificity. The difference in the repair phenotype of CPD between the HPRT gene and the APRT gene coincides with differences between both genes with regard to the DNA strand distribution of previously published UV-induced mutations.

Adenine Phosphoribosyltransferase↗
PubMed1992

Synthesis of novel thieno[2,3-d]pyrimidine, thieno[2,3-b]pyridine and thiazolo[3,2-a]thieno[2,3-d]pyrimidine derivatives and their effect on the production of mycotoxins.

The thiophene derivative 1 reacts with the active methylene reagents 2a-c to afford the thieno[2,3-d]pyrimidine derivatives 6a,b and 8, respectively. 1 reacts with phenacyl bromide 2d to afford the N-alkylation product 9 and reacts with phenacyl thiocyanate 2e to afford the N-(thiazol-2-yl) derivative 10, which was further cyclized into thiazolo[3,2-a]thieno[2,3-d]pyrimidine derivative 12. Compound 1 reacts also with the cinnamonitriles 3a,b to afford the thieno[2,3-b]pyridines 15a,b, respectively. 1 undergoes either acetylation or hydrolysis to afford the thieno[2,3-b]pyridine derivative 19 and the thiophene derivative 22, respectively. Some of the new compounds show inhibitory effect to the production of mycotoxins and to fungal growth.

Aspergillus↗
PubMed1996

Pyrrolo[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines as conformationally restricted analogues of the antibacterial agent trimethoprim.

Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR). This conformation of TMP was achieved by linking the 4-amino function to the methylene group by one- and two-carbon bridges. A pyrrolo[2,3-d]pyrimidine, a dihydro analogue, and a tetrahydropyrido[2,3-d]pyrimidine were synthesized and tested as inhibitors of DHFR. One analogue showed activity equivalent to that of TMP against DHFR from three species of bacteria. An X-ray crystal structure of this inhibitor bound to Escherichia coli DHFR was determined to evaluate the structural consequences of the conformational restriction.

Animals↗
PubMed1993

NMR structural studies on a nonnatural deoxyribonucleoside which mediates recognition of GC base pairs in pyrimidine-purine-pyrimidine DNA triplexes.

As a part of our ongoing efforts to define the structural aspects of unusual pairing alignments in DNA triplexes by nuclear magnetic resonance spectroscopy, we have examined the structural role of a nonnatural deoxyribonucleoside, P1, that has been shown to mediate the recognition of GC base pairs in pyrimidine-purine-pyrimidine DNA triplexes [Koh, J.S., & Dervan, P.B. (1992) J. Am. Chem Soc. 114, 1470]. A qualitative interpretation of the NMR data indicates that this analog of protonated cytosine is readily accommodated in the third strand segment of an intramolecular triplex system. Furthermore, the observed NOE patterns position the imino and amino protons of P1 opposite the N7 and O6 atoms of guanine, respectively, consistent with the previously proposed pairing scheme.

Base Composition↗
PubMed1989

Sequence specificity of DNA cleavage by bis(1,10-phenanthroline)copper(I): effects of single base pair transitions on the cleavage of preferred pyrimidine-purine-pyrimidine triplets.

The cleavage of DNA restriction fragments by bis(1,10-phenanthroline)copper(I) [[(OP)2CuI]+] is sequence dependent: the trimer TAT is most strongly preferred, while the trimer TGT and tetramers TAAT, TAGT, and CAGT are strongly to moderately preferred [Veal, J. M., & R. L. (1988) Biochemistry 27, 1822-1827]. [(OP)2CuI]+ cleavage of a series of oligonucleotide duplexes of the type 5'-CCCTPyPuPyCCCC-3'/3'-GGGAPuPyPuGGGG-5' (Py = pyrimidine; Pu = purine) was examined to determine the effects of purine substituents in the central triplet on specificity. The relative cleavage rates of different PyPuPy triplets in oligomers were similar to those observed for restriction fragments. The undecamer duplex containing the trimer TAT (TTATC) was most preferentially cleaved, predominantly at the central adenosine and the adjacent 3'-thymidine. Duplexes differing from TTATC by a single A.T----G.C transition in the central triplet were cleaved at significantly reduced rates relative to TTATC, the order of preference being TAT greater than TGT greater than TAC greater than CAT. By contrast, duplexes differing from TTATC by a single A.T----I.C transition were cleaved at rates similar to those for TTATC when the transition occurred at the 5'-pyrimidine or central purine [i.e., C(.I)AT and TIT]. A duplex containing the trimer TAC(.I) was cleaved at a reduced rate similar to the duplex containing TAC(.G). The guanine 2-amino group at positions 1 and 2, but not position 3, of a 5'-PyPuPy-3' trimer is therefore implicated as a strong inhibitor of DNA binding by the copper-phenanthroline complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Composition↗
PubMed1986

Inhibitors of human purine nucleoside phosphorylase. Synthesis, purine nucleoside phosphorylase inhibition, and T-cell cytotoxicity of 2,5-diaminothiazolo[5,4-d]pyrimidin-7(6H)-one and 2,5-diaminothiazolo[4,5-d]pyrimidin-7(6H)-one. Two thio isosteres of 8-aminoguanine.

8-Aminoguanine is a potent inhibitor of purine nucleoside phosphorylase (PNP) and also a substrate of PNP. Two thio isosteres of 8-aminoguanine, 2,5-diaminothiazolo[5,4-d]pyrimidin-7(6H)-one (2) and 2,4-diaminothiazolo[4,5-d]pyrimidin-7(6H)-one (3), which cannot be substrates of PNP, were synthesized and evaluated for their inhibitory activity against PNP. They were found to be weak inhibitors of PNP and to be noncytotoxic for MOLT-4 T-cells in culture.

Cell Division↗
PubMed1996

Guanine, pyrazolo[3,4-d]pyrimidine, and triazolo[4,5-d]pyrimidine (8-azaguanine) phosphonate acyclic derivatives as inhibitors of purine nucleoside phosphorylase.

Phosphonate acyclic derivates of guanines, pyrazolo[3,4-d]pyrimidines, and triazolo[4,5-d]-pyrimidines (8-azaguanines) are inhibitors of the enzyme purine nucleoside phosphorylase (PNPase) with Ki' values ranging from 0.05 to 1.6 microM. These compounds are enzymatically stable congeners of the potent PNPase inhibitor acyclovir diphosphate (53).

Azaguanine↗
PubMed2000

Randomized trial of regional plus systemic fluorinated pyrimidine compared with systemic fluorinated pyrimidine in treatment of colorectal liver metastases.

AIM: We report a prospective randomized study comparing survival, response and toxicity in colorectal liver metastasis (CLM) patients treated by either hepatic arterial floxuridine (HAI) plus continuous systemic fluorouracil/folinic acid or systemic fluorouracil/folinic acid. METHODS: Eighty-four CLM patients received either HAI plus systemic fluorouracil/folinic acid or systemic fluorouracil/ folinic acid. RESULTS: Significantly more HAI plus systemic, compared with systemic only, patients developed WHO grade 3 or 4 diarrhoea (P=0.004), but significant quality of life differences were not detected. Liver metastasis partial response at 4 months after randomization was significantly greater (P=0.003) in HAI plus systemic (13/29, 45%) compared with systemic only (7/30, 23%) patients. There was no significant difference between groups in the proportion of patients who died from extrahepatic disease progression, or in survival. CONCLUSION: Combining regional with systemic fluorinated pyrimidines did not improve survival compared with systemic fluorinated pyrimidine.

Aged↗
PubMed2003

The molecular and supramolecular structures of the isomeric compounds 5,7-dimethoxyimidazo[1,2-c]pyrimidine and 7-methoxy-1-methylimidazo[1,2-a]pyrimidin-5(1H)-one.

The supramolecular structures of the isomeric compounds 5,7-dimethoxyimidazo[1,2-c]pyrimidine, C(8)H(9)N(3)O(2), (I), and 7-methoxy-1-methylimidazo[1,2-a]pyrimidin-5(1H)-one, C(8)H(9)N(3)O(2), (II), are determined by weak C-H.N and C-H.O hydrogen bonds in (I), which generate alternating linked centrosymmetric R(2)(2)(8) and R(2)(2)(10) rings that form a ribbon running parallel to the c axis, and by C-H.O bonds in (II), which link the molecules into sheets comprising centrosymmetric R(2)(2)(10) and R(4)(4)(22) rings.

Journal Article↗
PubMed2004

Racemic 5-(4-chlorophenyl)-2-methoxyindeno[1',2':2,3]pyrido[5,6-d]pyrimidine-4,6(3H,5H)-dione-dimethylformamide (1/1) and (5RS,5aSR,10bSR)-10b-hydroxy-2-methoxy-5-(4-methoxyphenyl)-5a,10b-dihydroindeno[1',2':2,3]pyrido[5,6-d]pyrimidine-4,6(3H,5H)-dione-dimethylformamide (1/1): chains of rings generated by N-H...O and C-H...pi(arene) hydrogen bonds.

5-(4-Chlorophenyl)-2-methoxyindeno[1',2':2,3]pyrido[5,6-d]pyrimidine-4,6(3H,5H)-dione crystallizes as a 1:1 dimethylformamide solvate, C21H14ClN3O3.C3H7NO. The heterocyclic molecules contain a planar fused-ring system and they are linked by paired N-H...O hydrogen bonds [H...O = 1.85 A, N.O = 2.735 (4) A and N-H...O = 179 degrees ] into centrosymmetric dimers, which are themselves linked into chains by a single C-H.pi(arene) hydrogen bond. 10b-Hydroxy-2-methoxy-5-(4-methoxyphenyl)-5a,10b-dihydroindeno[1',2':2,3]pyrido[5,6-d]pyrimidine-4,6(3H,5H)-dione also crystallizes as a 1:1 dimethylformamide solvate, C22H19N3O5.C3H7NO. The heterocyclic molecules contain a sharply folded fused-ring system and they are linked by two independent N-H...O hydrogen bonds [H...O = 1.92 and 2.18 A, N...O = 2.801 (2) and 3.051 (2) A, and N-H...O = 175 and 173 degrees ] into chains of rings. In both compounds, the dimethylformamide molecules are pendent from the chains, linked via N-H...O and O-H...O hydrogen bonds, respectively.

Journal Article↗
PubMed1976

Deoxyribosyl transfer catalysis with trans-N-deoxyribosylase. Kinetic study of purine(pyrimidine) to pyrimidine(purine) trans-N-deoxyribosylase.

Kinetic studies were carried out in order to investigate the enzymic mechanism of a 215-fold-purified purine(pyrimidine) nucleoside: purine(pyrimidine) deoxyribosyl transferase fraction from Lactobacillus helveticus. A variety of natural deoxyribonucleosides and bases were used as substrates. Initial velocity, product inhibition and isotopic exchange studies are consistent with a ping-pong bi-bi mechanism. The kinetic parameters are used to show that this fraction is free from any contamination by a specific purine nucleoside: purine deoxyribosyl transferase also found in the same strain of L. helveticus.

Adenine↗
PubMed1979

Synthesis and anti-inflammatory properties of some pyrrolo(1H,3H)[3,4-d]pyrimidin-2-ones and pyrrolo(1H,6H)[3,4-d]pyrimidin-2-ones.

The unequivocal synthesis of some terms belonging to the two isomeric classes of the pyrrolo(1H,3H)[3,4-d]pyrimidin-2-ones and of the pyrrolo(1H,6H)[3,4-d]pyrimidin-2-ones is reported. Some of these compounds are active in inhibiting the development of the carrageenin edema, of the granuloma cotton pellet and of the adjuvant arthritis in the rat when administered orally.

Animals↗
PubMed1985

Unique pyrimidine 2D-COSY aromatic cross-peaks as monitors of pyrimidine environments and mobility in oligo- and polynucleotides.

Only cytosine contains two adjacent aromatic protons that give rise to cross-peaks in the aromatic region of 2D-COSY spectra of oligodeoxynucleotides. In two GC-containing sequences several such cross-peaks were resolved. The intensity of these cross-peaks is a sensitive monitor of local mobility, and upon the addition of the intercalating drug daunomycin selective intensity losses were observed, indicating binding to specific GC base pairs. We have also monitored the 2D-COSY cross-peaks from mobile pyrimidine bases in tRNA (Phe) as a function of temperature.

Base Composition↗