Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid

Diane H. Boschelli, Stephanie Webber, John M. Whiteley, Arnold L. Oronsky, S. S. Kerwar

Research output: Contribution to journalArticle

Abstract

The synthesis of the antifolate 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) has been modified. It is prepared from 2-acetamido-6-formyl-4(3H)-pyrido[2,3-b]pyrimidone and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)]phenylmethyl]-triphenylphosphonium bromide. The synthesis proceeds via a sodium hydride promoted Wittig condensation in 1-methyl-2-pyrrolidone followed by catalytic reduction, mild base hydrolysis, and acid precipitation of the product. Synthesis of DDATHF is achieved in a total of seven steps from commercially available reagents. DDATHF is transported effectively into CCRF-CEM cells and inhibits growth of both human (CEM) and murine (L1210) cells in culture. Studies reported here support the view that methotrexate and DDATHF are transported via a shared transport mechanism.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume265
Issue number1
DOIs
StatePublished - Aug 15 1988
Externally publishedYes

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Pyrimidinones
Folic Acid Antagonists
Bromides
Methotrexate
Condensation
Hydrolysis
Cell Culture Techniques
Acids
lometrexol
Growth
N-methylpyrrolidone
2-pyrrolidone
sodium hydride

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid. / Boschelli, Diane H.; Webber, Stephanie; Whiteley, John M.; Oronsky, Arnold L.; Kerwar, S. S.

In: Archives of Biochemistry and Biophysics, Vol. 265, No. 1, 15.08.1988, p. 43-49.

Research output: Contribution to journalArticle

Boschelli, Diane H. ; Webber, Stephanie ; Whiteley, John M. ; Oronsky, Arnold L. ; Kerwar, S. S. / Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid. In: Archives of Biochemistry and Biophysics. 1988 ; Vol. 265, No. 1. pp. 43-49.
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AU - Kerwar, S. S.

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AB - The synthesis of the antifolate 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) has been modified. It is prepared from 2-acetamido-6-formyl-4(3H)-pyrido[2,3-b]pyrimidone and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)]phenylmethyl]-triphenylphosphonium bromide. The synthesis proceeds via a sodium hydride promoted Wittig condensation in 1-methyl-2-pyrrolidone followed by catalytic reduction, mild base hydrolysis, and acid precipitation of the product. Synthesis of DDATHF is achieved in a total of seven steps from commercially available reagents. DDATHF is transported effectively into CCRF-CEM cells and inhibits growth of both human (CEM) and murine (L1210) cells in culture. Studies reported here support the view that methotrexate and DDATHF are transported via a shared transport mechanism.

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