Dihydrofolate reductase inhibition by 2,4-diaminotriazines: A structure-activity study

Dietrich, Stephen W.; Smith, R. Nelson; Fukunaga, James Y.; Olney, Mary B.; Hansch, Corwin

doi:10.1016/0003-9861(79)90655-6

Cited by 17 publications

(3 citation statements)

References 26 publications

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“…Further support for this conclusion comes from our results on dicyclanil, a pyrimidine analog and biological mimic of cyromazine with much higher activity (Kristinson, 1994), that was also inactive on DHFR from both Drosophila and hen. Overall, these negative results are surprising in the light of findings that effective inhibitors of DHFR are found among aminotriazines and aminopyrimidines carrying aryl substituents (Dietrich et al, 1979;Wierenga et al, 2000).…”

Section: Discussionmentioning

confidence: 95%

Candidate target mechanisms of the growth inhibitor cyromazine: Studies of phenylalanine hydroxylase, puparial amino acids, and dihydrofolate reductase in dipteran insects

Bel

Wiesner

Kayser

2000

Arch. Insect Biochem. Physiol.

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Cyromazine, an insect growth regulator, affects larval and pupal cuticles in dipterans and some other insects. The mode of action of this aminotriazine is not known yet, though it has been shown not to inhibit the synthesis of chitin and cuticular proteins. Cyromazine may, however, act on some step(s) of sclerotization of the cuticle. In the present study, we have analyzed the key enzyme for the production of sclerotization agents, phenylalanine hydroxylase (PAH), using the enzyme from Drosophila, a cyromazine-sensitive insect. PAH was studied in vitro with cyromazine and three biologically less active derivatives at concentrations ranging from 1 microM to 1 mM. None of the compounds did significantly affect PAH activity. Nor did cyromazine, fed to last instar larvae of Musca domestica, change the relative content of phenylalanine and tyrosine, or the total amount and profile of amino acids of puparial cuticles, which showed a larviform shape typical for cyromazine intoxication. Taken together, this study does not support the hypothesis that phenylalanine hydroxylase represents a target site of cyromazine. In additional studies, the conflicting results, as reported by others, on in vitro inhibition of dihydrofolate reductase (DHFR) by cyromazine were re-examined using the enzymes from larvae of the blowfly, Protophormia terraenovae, and from hen liver. There was no significant inhibition of either DHFR at 100 microM by cyromazine as well as by dicylanil, a pyrimidine analog that is biologically more active than cyromazine. In conclusion, the mode of action of cyromazine remains completely open.

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Section: Discussionmentioning

confidence: 95%

Candidate target mechanisms of the growth inhibitor cyromazine: Studies of phenylalanine hydroxylase, puparial amino acids, and dihydrofolate reductase in dipteran insects

Bel

Wiesner

Kayser

2000

Arch. Insect Biochem. Physiol.

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“…(3) = 37; r = 0.065; s = 0.707; F1>36 = 0.14 log 1/C = 1.27 (±0.25) -1.68 (±0.32) log (/M0* + 1) + 8.14 (±0.18) (4) = 37; r = 0.879; s = 0.347; F1]33 = 58.0; log ß = -0.361; 7T0 = 0.85 (0.59-1.13) log 1/C = 1.32 (±0.22) -1.70 (±0.27) log (/M0* + 1) + 0.44 (±0.19) I + 8.10 (±0.18) (5) = 37; r = 0.929; s = 0.274; F1j32 = 20.9; log ß = -0.215; x0 = 0.76 (0.52-1.00) log 1/C = 1.34 (±0.20) -1.69 (±0.25) log (/M0* + 1) + 0.58 (±0.21) I + 0.75 (±0.59) + 7.87 (±0.22) (6) = 37; r = 0.942; s = 0.254; Fli31 = 6.68; log ß = -0.249; 0 = 0.82 (0.59-1.05) the inhibition of L5178Y cells by congeners I. Equation 6a is the correlation for all congeners in Table I.…”

Section: Resultsmentioning

confidence: 99%

Comparison of quantitative structure-activity relationships of the inhibition of leukemia cells in culture with the inhibition of dihydrofolate reductase from leukemia cells and other cell types

Khwaja¹,

Pentecost²,

Selassie³

et al. 1982

J. Med. Chem.

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A set of 2,4-diamino-5-(3-X-phenyl)-s-triazines was used to inhibit the growth of tumor cells (L5178 leukemia) in culture. The molar concentration (C) of triazine causing 50% reduction in the rate of cell growth was used to develop a quantitative structure-activity relationship: log 1/C = 1.32 pi - 1.70 log (beta.10 pi + 1) + 0.44I + 8.10, where pi is the hydrophobic constant for X, beta is a disposable parameter, and I is an indicator variable for congeners containing a -CH2Z-C6H4-Y moiety (Z = O or NH). This equation is compared with similar equations derived for the inhibition of dihydrofolate reductase from leukemia cells and bovine liver.

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“…Bovine Liver DHFR QSAR. Equations 5-8 for the log (l/Kupp) = 0.36 (±0.14) 3,5 + 5.32 (±0.15) (5) = 35; r = 0.670; inhibition of bovine DHFR by benzylpyrimidines, when compared with eq 3, bring out the differences in the character of enzymatic space in the region of the active sites of the two enzymes. One data point (no.…”

Section: Resultsmentioning

confidence: 99%

Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted-benzyl)-2,4-diaminopyrimidines

Li¹,

Dietrich²,

Hansch³

1981

J. Med. Chem.

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In our previous publication (Blaney, J. M.; Dietrich, S. W.; Reynolds, M. A.; Hansch, C. J. Med. Chem. 1979, 22, 614), correlation equations were presented for the inhibition of bovine liver and Escherichia coli dihydrofolate reductase (DHFR) by 5-(substituted benzyl)-2,4-diaminopyrimidines. These equations brought out differences in the way these two enzymes interact with substituents, which explain the high selectivity of drugs like trimethoprim. We have tested and further developed these equations in this report. It is of particular interest that our previously published correlation equation for E. coli DHFR accurately predicted the potency of a commercial competitor of trimethoprim (tetroxoprim) now in clinical use. We believe that new and effective competitors for trimethoprim can be designed by means of the two correlation equations.

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Dihydrofolate reductase inhibition by 2,4-diaminotriazines: A structure-activity study

Cited by 17 publications

References 26 publications

Candidate target mechanisms of the growth inhibitor cyromazine: Studies of phenylalanine hydroxylase, puparial amino acids, and dihydrofolate reductase in dipteran insects

Candidate target mechanisms of the growth inhibitor cyromazine: Studies of phenylalanine hydroxylase, puparial amino acids, and dihydrofolate reductase in dipteran insects

Comparison of quantitative structure-activity relationships of the inhibition of leukemia cells in culture with the inhibition of dihydrofolate reductase from leukemia cells and other cell types

Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted-benzyl)-2,4-diaminopyrimidines

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