Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line.

doi:10.1021/JM00131A009

Paper

Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line.

Published Nov 1, 1989 · R. Griffin, M. Meek, C. Schwalbe

Journal of medicinal chemistry

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15

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0

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Abstract

A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position, the corresponding 3-amino, 3-azido, or unsubstituted analogues proving only weakly active or inactive as DHFR inhibitors. Selected compounds were also screened in vivo against a methotrexate-resistant tumor, the M5076 murine reticulosarcoma, and antitumor activity in general paralleled activity against DHFR, the (3,4-dichlorobenzyl)amino analogue 26 proving the least toxic compound to exhibit significant antitumor activity. The X-ray crystal structure of the ethanesulfonic acid salt of the N-methylbenzylamino compound 29 has been determined to facilitate future molecular modeling studies in this new series of DHFR inhibitors.

In Vitro Study

Study Snapshot

A new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors shows potential as methotrexate-resistant tumor cell inhibitors, with the least toxic compound showing significant antitumor activity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line.

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References

Citations

Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.

Pyr analogues show promising anti-cancer activity, with two identified as potential lead candidates, 32 and 34, showing potent DHFR inhibitory activity at low concentrations.

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study

Methylbenzoprim, a low-cost synthetic drug, shows potential as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.

Recent Developments in Ghrelin Receptor Ligands

Recent developments in ghrelin receptor ligands show potential for both clinical and therapeutic applications in neuroendocrine and metabolic research.

Dihydrofolate reductase as a target for chemotherapy in parasites.

Selective DHFR inhibition is crucial for effective parasitic chemotherapy, but current treatments face high costs and resistance issues.

Structural characteristics of small-molecule antifolate compounds

Small-molecule antifolate compounds show promising molecular conformations and supramolecular interactions, aiding in drug design for infections and cancer treatments.

An Expeditious Synthesis of 6-Alkyl-5-(4′-amino-phenyl)-pyrimidine-2,4-diamines

This study presents a rapid synthesis of 6-alkyl substituted-5-(4′-amino-phenyl)-pyrimidine-2,4-diamines, enabling the study of their structure-activity relationships with current anti-tumor and anti-malarial compounds.

Structural Studies on Bioactive Compounds. Part 37.1 Suzuki Coupling of Diaminopyrimidines: A New Synthesis of the Antimalarial Drug Pyrimethamine †

Suzuki reactions successfully synthesized the antimalarial drug pyrimethamine by coupling 2,4-diamino-6-ethyl-5-iodopyrimidine with 4-chlorobenzeneboronic acid.

Chemical synthesis and biological properties of novel fluorescent antifolates in Pgp- and MRP-overexpressing tumour cell lines.

Novel fluorescent antifolates show potential in treating methotrexate-resistant lung cancer, but may be substrates for both P-glycoprotein and MRP resistance mechanisms, making them susceptible to alternative mechanisms.