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Chemical Compound Review

PDDF     2-[[4-[(2-amino-4-oxo-1H- quinazolin-6...

Synonyms: CHEMBL422395, CB-3717, CHEBI:129325, ICI-155387, NSC-327182, ...
 
 
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Disease relevance of CB 3717

 

High impact information on CB 3717

  • CB 3717 was as active as MTX on both cell lines in inhibiting colony formation, but 20-100 times less potent [5].
  • Since after 16 h treatment with MTX or CB 3717 cells were completely viable, as assessed by [3H]thymidine release, trypan blue exclusion test, and 51Cr release, DNA damage appears to be an early event preceding cell death and may be a feature of the killing ability of the drugs [5].
  • In the presence of dUMP, a tightly bound complex rapidly formed between isolated pure TS and the pentaglutamate of CB 3717 but not the monoglutamate form of this compound [6].
  • We have investigated some unusual aspects of the inhibition of mammalian thymidylate synthase (TS) by the folate antimetabolite, 10-propargyl-5,8-dideaza-folic acid (CB 3717) [6].
  • Exposure of intact mouse L1210 cells to CB 3717 resulted in inactivation of cellular TS activity, yet desalted cytosol preparations from these cells retained the ability to bind FdUMP [6].
 

Chemical compound and disease context of CB 3717

 

Biological context of CB 3717

  • From our results, we conclude that binding of CB 3717 metabolites to one subunit of L1210 TS modified the conformation of the second active site of this enzyme so that it retained the ability to bind 5-fluro-2'-deoxyuridine-5'-monophosphate (FdUMP) but not its catalytic activity [6].
  • CB 3717 and methotrexate-G2 are competitors for the same protein binding site [8].
  • The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation [9].
  • There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels [9].
  • Pharmacokinetic investigations have shown that alkaline diuresis does not alter CB 3717 plasma levels or urinary excretion and that satisfactory urinary alkalinization can be readily achieved [4].
 

Anatomical context of CB 3717

 

Associations of CB 3717 with other chemical compounds

  • Structural modifications at the pyrimidine ring and at the C9,N10-bridge region of the thymidylate synthase (TS) inhibitors N10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out [10].
  • Evidence for the influence of polyglutamation was also provided by the relatively low affinity of dideazofolates for thymidylate synthase (association constant equal to 1.4 and 1.7 x 10(7) M-1 for CB 3717 and CB 3819, respectively), whereas these compounds are known to be strong inhibitors of the enzyme in cells in their polyglutamated forms [8].
  • A microcalorimetric method was used for the direct study of the interaction of methotrexate, its metabolites, and new antifolates N10-propargyl-5,8-dideazafolate (CB 3717) and 2-methyl,2-desamino N10-propargyl-5,8-dideazafolate (CB 3819), with thymidylate synthase [8].
  • A dose regime of 200 mg CB3717 kg-1 body wt day-1 for 5 days caused a significant reduction in growth rate, as measured by relative serum AFP, of both xenografts; PLC/PRF/5 derived xenograft growth was also inhibited by 125 mg CB 3717 kg-1 day-1 for 5 days [11].
  • Inhibition of thymidylate synthetase by the new quinazoline antifolate, CB 3717; enzyme purification and kinetics [12].
 

Gene context of CB 3717

 

Analytical, diagnostic and therapeutic context of CB 3717

  • Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m2 CB 3717 [9].
  • Following a 12-hour exposure of L1210 cells to 50 microM [3H]CB 3717, 30% of the extractable radioactivity could be accounted for as CB 3717 tetra- and pentaglutamate, as determined by high-pressure liquid chromatography (HPLC) analyses [4].

References

  1. Intestinal alkaline phosphatase isoenzyme in patients with primary liver cancer during treatment with N10-propargyl 5, 8-dideazafolic acid (CB 3717). Buamah, P.K., Skillen, A.W., Cassells-Smith, A.J., James, O.F., Harris, A.L. Journal of surgical oncology. (1988) [Pubmed]
  2. Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer. Cantwell, B.M., Macaulay, V., Harris, A.L., Kaye, S.B., Smith, I.E., Milsted, R.A., Calvert, A.H. European journal of cancer & clinical oncology. (1988) [Pubmed]
  3. Polyamines in testosterone-induced hypertrophic and antifolate-induced hyperplastic mouse kidney. Differential effect of alpha-difluoromethylornithine. Manteuffel-Cymborowska, M., Chmurzyńska, W., Grzelakowska-Sztabert, B. Biochim. Biophys. Acta (1993) [Pubmed]
  4. Recent preclinical and clinical studies with the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB 3717). Calvert, A.H., Newell, D.R., Jackman, A.L., Gumbrell, L.A., Sikora, E., Grzelakowska-Sztabert, B., Bishop, J.A., Judson, I.R., Harland, S.J., Harrap, K.R. NCI monographs : a publication of the National Cancer Institute. (1987) [Pubmed]
  5. Accumulation of DNA strand breaks in cells exposed to methotrexate or N10-propargyl-5,8-dideazafolic acid. Lorico, A., Toffoli, G., Boiocchi, M., Erba, E., Broggini, M., Rappa, G., D'Incalci, M. Cancer Res. (1988) [Pubmed]
  6. Quinazoline folate analogs inhibit the catalytic activity of thymidylate synthase but allow binding of 5-fluorodeoxyuridylate. Keyomarsi, K., Moran, R.G. J. Biol. Chem. (1990) [Pubmed]
  7. Up-regulation of spermidine/spermine N1-acetyltransferase (SSAT) expression is a part of proliferative but not anabolic response of mouse kidney. Dudkowska, M., Stachurska, A., Grzelakowska-Sztabert, B., Manteuffel-Cymborowska, M. Acta Biochim. Pol. (2002) [Pubmed]
  8. Thermodynamic study of the interaction of methotrexate, its metabolites, and new antifolates with thymidylate synthase: influence of FdUMP. Gilli, R., Lopez, C., Sari, J.C., Briand, C. Biochem. Pharmacol. (1990) [Pubmed]
  9. The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717). Alison, D.L., Newell, D.R., Sessa, C., Harland, S.J., Hart, L.I., Harrap, K.R., Calvert, A.H. Cancer Chemother. Pharmacol. (1985) [Pubmed]
  10. Folate analogues. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogues of N10-propargyl-5,8-dideazafolic acid. Li, S.W., Nair, M.G., Edwards, D.M., Kisliuk, R.L., Gaumont, Y., Dev, I.K., Duch, D.S., Humphreys, J., Smith, G.K., Ferone, R. J. Med. Chem. (1991) [Pubmed]
  11. Inhibition of the growth of human hepatocellular carcinoma in vitro and in athymic mice by a quinazoline inhibitor of thymidylate synthase, CB3717. Curtin, N.J., Harris, A.L., James, O.F., Bassendine, M.F. Br. J. Cancer (1986) [Pubmed]
  12. Inhibition of thymidylate synthetase by the new quinazoline antifolate, CB 3717; enzyme purification and kinetics. Jackman, A.L., Calvert, A.H., Hart, L.I., Harrap, K.R. Adv. Exp. Med. Biol. (1984) [Pubmed]
  13. Arginine and ornithine metabolizing enzymes in testosterone-induced hypertrophic mouse kidney. Manteuffel-Cymborowska, M., Chmurzyńska, W., Peska, M., Grzelakowska-Sztabert, B. Int. J. Biochem. Cell Biol. (1995) [Pubmed]
  14. Mechanism of the induction of the differentiation of HL-60 leukemia cells by antifolates. Sokoloski, J.A., Beardsley, G.P., Sartorelli, A.C. Cancer Commun. (1989) [Pubmed]
  15. Cross-talk between steroid-receptor-mediated and cell-membrane-receptor-mediated signalling pathways results in the in vivo modulation of c-Met and ornithine decarboxylase gene expression in mouse kidney. Dudkowska, M., Stachurska, A., Chmurzyska, W., Grzelakowska-Sztabert, B., Manteuffel-Cymborowska, M. Biochem. J. (2001) [Pubmed]
  16. Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression. Stachurska, A., Dudkowska, M., Czopek, A., Manteuffel-Cymborowska, M., Grzelakowska-Sztabert, B. Biochim. Biophys. Acta (2004) [Pubmed]
  17. Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717. Sessa, C., Zucchetti, M., Ginier, M., Willems, Y., D'Incalci, M., Cavalli, F. European journal of cancer & clinical oncology. (1988) [Pubmed]
 
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