Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino- 5-ethylpyrrolo[2,3-d]pyrimidines as antifolates

Aleem Gangjee, Yibin Zeng, Tina Talreja, John J. McGuire, Roy L. Kisliuk, Sherry Queener

Research output: Contribution to journalArticle

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Abstract

The classical antifolate N-{4-[(2,4-diamino-5-ethyl-7H-pyrrolo[2,3-d] pyrimidin-6-yl)sulfanyl]benzoyl}-L-glutamic acid (2) and 15 nonclassical analogues (3-17) were synthesized as potential dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. 5-Ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4- diamine (20) served as the key intermediate to which various aryl thiols and a heteroaryl thiol were appended at the 6-position via an oxidative addition reaction. The classical analogue 2 was synthesized by coupling the benzoic acid derivative 18 with diethyl L-glutamate followed by saponification. The classical compound 2 was an excellent inhibitor of human DHFR (IC50 = 66 nM) as well as a two digit nanomolar (< 100 nM) inhibitor of the growth of several tumor cells in culture. Some of the nonclassical analogues were potent and selective inhibitors of DHFR from two pathogens (Toxoplasma gondii and Mycobacterium avium) that cause opportunistic infections in patients with compromised immune systems.

Original languageEnglish
Pages (from-to)3046-3053
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number13
DOIs
StatePublished - Jun 28 2007

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Folic Acid Antagonists
Pyrimidines
Sulfhydryl Compounds
Glutamic Acid
Saponification
Growth Inhibitors
Tetrahydrofolate Dehydrogenase
Addition reactions
Benzoic Acid
Diamines
Immune system
Pathogens
Cell culture
Mycobacterium avium
Antineoplastic Agents
Tumors
Opportunistic Infections
Toxoplasma
Cells
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino- 5-ethylpyrrolo[2,3-d]pyrimidines as antifolates. / Gangjee, Aleem; Zeng, Yibin; Talreja, Tina; McGuire, John J.; Kisliuk, Roy L.; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 50, No. 13, 28.06.2007, p. 3046-3053.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Zeng, Yibin ; Talreja, Tina ; McGuire, John J. ; Kisliuk, Roy L. ; Queener, Sherry. / Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino- 5-ethylpyrrolo[2,3-d]pyrimidines as antifolates. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 13. pp. 3046-3053.
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