Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and mammalian dihydrofolate reductase

Andre Rosowsky, Ronald A. Forsch, Sherry Queener, Joseph R. Bertino

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Ten previously undescribed 2,4-diamino-6-(2- naphthylamino)methylpteridines with lipophilic chlorine or long-chain alkyl groups on the naphthyl moiety and either hydrogen or a methyl group on N10 were synthesized from the appropriate 2-naphthylamine or N-methyl-2- naphthylamine by reaction with 2-amino-5-chloromethylpyrazine-3-carbonitrile and ring closure with guanidine. One analogue with a methyl group at the 7- position was also prepared. The N10-unsubstituted analogues were consistently less active than the N10-methyl analogues as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase. However the potency of the series as a whole was relatively low against all three enzymes, with the best inhibitors giving IC50 values only in the 0.1-1.0 μM range and several giving IC50 values in the 10-100 μM range. Moreover, while several compounds with IC50 values of <10 μM showed some selectivity for the Pneumocystis carinii and/or Toxoplasma gondii enzyme relative to the rat liver enzyme, the magnitude of this effect was marginal (<4-fold). Assays were also performed against purified human dihydrofolate reductase and against wild-type and methotrexate-resistant human leukemic lymphoblasts in culture. Activity against the enzyme was very low, the best inhibitors giving only 50-70% inhibition at 10 μM. Although none of the compounds inhibited the growth of wild-type CEM cells by more than 20% at 1 μM, several were more active (60-75% inhibition at 1 μM) against the methotrexare-resistant subline CEM/MTX, which is defective in metho-trexate and reduced folate transport, than they were against the methotrexate- sensitive parental CEM cells. Overall the results suggest that 2,4-diamino- 6-substituted pteridines with chlorine or long-chain alkyl substituents in the 2-naphthyl moiety and hydrogen or a methyl group on N10 are not likely to be therapeutically useful agents.

Original languageEnglish
Pages (from-to)173-187
Number of pages15
JournalPteridines
Volume8
Issue number3
StatePublished - Sep 1997

Fingerprint

Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Toxoplasma
2-Naphthylamine
Inhibitory Concentration 50
Chlorine
Enzymes
Methotrexate
Liver
Rats
Hydrogen
Pteridines
Guanidine
Folic Acid
Assays
2,4-diaminopteridine
Growth

Keywords

  • 2,4-Diaminoptefidines
  • Bulky lipophilic group
  • Dihydrofolate reductase
  • Pneumocystis carinii
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and mammalian dihydrofolate reductase. / Rosowsky, Andre; Forsch, Ronald A.; Queener, Sherry; Bertino, Joseph R.

In: Pteridines, Vol. 8, No. 3, 09.1997, p. 173-187.

Research output: Contribution to journalArticle

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title = "Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and mammalian dihydrofolate reductase",
abstract = "Ten previously undescribed 2,4-diamino-6-(2- naphthylamino)methylpteridines with lipophilic chlorine or long-chain alkyl groups on the naphthyl moiety and either hydrogen or a methyl group on N10 were synthesized from the appropriate 2-naphthylamine or N-methyl-2- naphthylamine by reaction with 2-amino-5-chloromethylpyrazine-3-carbonitrile and ring closure with guanidine. One analogue with a methyl group at the 7- position was also prepared. The N10-unsubstituted analogues were consistently less active than the N10-methyl analogues as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase. However the potency of the series as a whole was relatively low against all three enzymes, with the best inhibitors giving IC50 values only in the 0.1-1.0 μM range and several giving IC50 values in the 10-100 μM range. Moreover, while several compounds with IC50 values of <10 μM showed some selectivity for the Pneumocystis carinii and/or Toxoplasma gondii enzyme relative to the rat liver enzyme, the magnitude of this effect was marginal (<4-fold). Assays were also performed against purified human dihydrofolate reductase and against wild-type and methotrexate-resistant human leukemic lymphoblasts in culture. Activity against the enzyme was very low, the best inhibitors giving only 50-70{\%} inhibition at 10 μM. Although none of the compounds inhibited the growth of wild-type CEM cells by more than 20{\%} at 1 μM, several were more active (60-75{\%} inhibition at 1 μM) against the methotrexare-resistant subline CEM/MTX, which is defective in metho-trexate and reduced folate transport, than they were against the methotrexate- sensitive parental CEM cells. Overall the results suggest that 2,4-diamino- 6-substituted pteridines with chlorine or long-chain alkyl substituents in the 2-naphthyl moiety and hydrogen or a methyl group on N10 are not likely to be therapeutically useful agents.",
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AU - Bertino, Joseph R.

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AB - Ten previously undescribed 2,4-diamino-6-(2- naphthylamino)methylpteridines with lipophilic chlorine or long-chain alkyl groups on the naphthyl moiety and either hydrogen or a methyl group on N10 were synthesized from the appropriate 2-naphthylamine or N-methyl-2- naphthylamine by reaction with 2-amino-5-chloromethylpyrazine-3-carbonitrile and ring closure with guanidine. One analogue with a methyl group at the 7- position was also prepared. The N10-unsubstituted analogues were consistently less active than the N10-methyl analogues as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase. However the potency of the series as a whole was relatively low against all three enzymes, with the best inhibitors giving IC50 values only in the 0.1-1.0 μM range and several giving IC50 values in the 10-100 μM range. Moreover, while several compounds with IC50 values of <10 μM showed some selectivity for the Pneumocystis carinii and/or Toxoplasma gondii enzyme relative to the rat liver enzyme, the magnitude of this effect was marginal (<4-fold). Assays were also performed against purified human dihydrofolate reductase and against wild-type and methotrexate-resistant human leukemic lymphoblasts in culture. Activity against the enzyme was very low, the best inhibitors giving only 50-70% inhibition at 10 μM. Although none of the compounds inhibited the growth of wild-type CEM cells by more than 20% at 1 μM, several were more active (60-75% inhibition at 1 μM) against the methotrexare-resistant subline CEM/MTX, which is defective in metho-trexate and reduced folate transport, than they were against the methotrexate- sensitive parental CEM cells. Overall the results suggest that 2,4-diamino- 6-substituted pteridines with chlorine or long-chain alkyl substituents in the 2-naphthyl moiety and hydrogen or a methyl group on N10 are not likely to be therapeutically useful agents.

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