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

doi:10.1016/0003-9861(88)90369-4

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 journal › Article › peer-review

17 Scopus citations

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 language	English (US)
Pages (from-to)	43-49
Number of pages	7
Journal	Archives of Biochemistry and Biophysics
Volume	265
Issue number	1
DOIs	https://doi.org/10.1016/0003-9861(88)90369-4
State	Published - Aug 15 1988
Externally published	Yes

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology

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10.1016/0003-9861(88)90369-4

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@article{c3e944033fac4fc1b2140ddb85373fea,

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

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.",

author = "Boschelli, {Diane H.} and Stephanie Webber and Whiteley, {John M.} and Oronsky, {Arnold L.} and Kerwar, {S. S.}",

note = "Funding Information: 1 S.W. and J.M.W. were supported in part by Grants CA 38849, CA 11778, and GM 22125 from the National Institutes of Health. a To whom correspondence should be addressed. {\textquoteright} Abbreviations used: DMF, dimethylformamide; NMP, l-methyl-Z-pyrrolidone; DDATHF, 5,10-dideaza-5,6,7,8-tetrahydrofolic acid; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); MTX, methotrexate; PBS, phosphate-buffered saline; Hepes, 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; DHFR, dihydrofolate reductase; GAR, glycinamide ribonucleotide.",

year = "1988",

month = aug,

day = "15",

doi = "10.1016/0003-9861(88)90369-4",

language = "English (US)",

volume = "265",

pages = "43--49",

journal = "Archives of Biochemistry and Biophysics",

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T1 - Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid

AU - Boschelli, Diane H.

AU - Webber, Stephanie

AU - Whiteley, John M.

AU - Oronsky, Arnold L.

AU - Kerwar, S. S.

N1 - Funding Information: 1 S.W. and J.M.W. were supported in part by Grants CA 38849, CA 11778, and GM 22125 from the National Institutes of Health. a To whom correspondence should be addressed. ’ Abbreviations used: DMF, dimethylformamide; NMP, l-methyl-Z-pyrrolidone; DDATHF, 5,10-dideaza-5,6,7,8-tetrahydrofolic acid; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); MTX, methotrexate; PBS, phosphate-buffered saline; Hepes, 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; DHFR, dihydrofolate reductase; GAR, glycinamide ribonucleotide.

PY - 1988/8/15

Y1 - 1988/8/15

N2 - 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.

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

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