Stereospecific synthesis of D-1-fluorodeoxyglycerol 3-phosphate and its effects on glycerol 3-phosphate dehydrogenase

Gurdev S. Ghangas, Thomas P Fondy

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

D-1-Fluoro-1-deoxyglycerol 3-phosphate was prepared starting from D-mannitol by the intermediate synthesis of D-2,3-isopropylideneglycerol, D-1-tosyl-2,3-isopropylideneglycerol, D-1-fluorodeoxy-2,3-isopropylideneglycerol, D-1-fluorodeoxyglycerol, and D-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester. The corresponding racemic compounds were also prepared starting from glycerol. The identity of DL-1-fluorodeoxyglycerol, DL-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester, and DL-1-fluorodeoxyglycerol 3-phosphate was confirmed by comparison of chemical and physical properties of the compounds synthesized by this route, to the corresponding compounds prepared by ring opening of epifluorohydrin by aqueous acid, dibenzylphosphoric acid, or phosphoric acid, respectively. Nuclear magnetic resonance spectra of intermediates and of the final product are presented and analyzed. Racemic 1-fluorodeoxyglycerol 3-phosphate synthesized from glycerol is a substrate for rabbit muscle NAD-linked glycerol 3-phosphate dehydrogenase, and is indistinguishable in its kinetic behavior from the compound synthesized from epifluorohydrin. D-1-Fluorodeoxyglycerol 3-phosphate possesses no substrate activity with the enzyme, and inhibits the oxidation of L-glycerol 3-phosphate by the enzyme. The stereospecific synthetic route to D-1-fluorodeoxyglycerol 3-phosphate is readily applicable with slight modification to synthesis of the L enantiomorph. Availability of optically pure forms of D-and L-1-fluorodeoxyglycerol 3-phosphate will permit an examination of our suggestion that 1-fluoro analogs of glycerol 3-phosphate or dihydroxyacetone 3-phosphate or precursors that could generate them in vivo may be selectively toxic to cells lacking NAD-linked glycerol 3-phosphate dehydrogenase, which is a characteristic of many types of cancer cells.

Original languageEnglish (US)
Pages (from-to)3204-3210
Number of pages7
JournalBiochemistry
Volume10
Issue number17
StatePublished - 1971
Externally publishedYes

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Glycerolphosphate Dehydrogenase
Phosphates
Glycerol-3-Phosphate Dehydrogenase (NAD+)
NAD
Esters
Dihydroxyacetone Phosphate
L Forms
Acids
Poisons
Mannitol
Substrates
Enzymes
Glycerol
Chemical properties
Muscle
Magnetic Resonance Spectroscopy
Physical properties
Cells
Nuclear magnetic resonance
Availability

ASJC Scopus subject areas

  • Biochemistry

Cite this

Stereospecific synthesis of D-1-fluorodeoxyglycerol 3-phosphate and its effects on glycerol 3-phosphate dehydrogenase. / Ghangas, Gurdev S.; Fondy, Thomas P.

In: Biochemistry, Vol. 10, No. 17, 1971, p. 3204-3210.

Research output: Contribution to journalArticle

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abstract = "D-1-Fluoro-1-deoxyglycerol 3-phosphate was prepared starting from D-mannitol by the intermediate synthesis of D-2,3-isopropylideneglycerol, D-1-tosyl-2,3-isopropylideneglycerol, D-1-fluorodeoxy-2,3-isopropylideneglycerol, D-1-fluorodeoxyglycerol, and D-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester. The corresponding racemic compounds were also prepared starting from glycerol. The identity of DL-1-fluorodeoxyglycerol, DL-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester, and DL-1-fluorodeoxyglycerol 3-phosphate was confirmed by comparison of chemical and physical properties of the compounds synthesized by this route, to the corresponding compounds prepared by ring opening of epifluorohydrin by aqueous acid, dibenzylphosphoric acid, or phosphoric acid, respectively. Nuclear magnetic resonance spectra of intermediates and of the final product are presented and analyzed. Racemic 1-fluorodeoxyglycerol 3-phosphate synthesized from glycerol is a substrate for rabbit muscle NAD-linked glycerol 3-phosphate dehydrogenase, and is indistinguishable in its kinetic behavior from the compound synthesized from epifluorohydrin. D-1-Fluorodeoxyglycerol 3-phosphate possesses no substrate activity with the enzyme, and inhibits the oxidation of L-glycerol 3-phosphate by the enzyme. The stereospecific synthetic route to D-1-fluorodeoxyglycerol 3-phosphate is readily applicable with slight modification to synthesis of the L enantiomorph. Availability of optically pure forms of D-and L-1-fluorodeoxyglycerol 3-phosphate will permit an examination of our suggestion that 1-fluoro analogs of glycerol 3-phosphate or dihydroxyacetone 3-phosphate or precursors that could generate them in vivo may be selectively toxic to cells lacking NAD-linked glycerol 3-phosphate dehydrogenase, which is a characteristic of many types of cancer cells.",
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N2 - D-1-Fluoro-1-deoxyglycerol 3-phosphate was prepared starting from D-mannitol by the intermediate synthesis of D-2,3-isopropylideneglycerol, D-1-tosyl-2,3-isopropylideneglycerol, D-1-fluorodeoxy-2,3-isopropylideneglycerol, D-1-fluorodeoxyglycerol, and D-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester. The corresponding racemic compounds were also prepared starting from glycerol. The identity of DL-1-fluorodeoxyglycerol, DL-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester, and DL-1-fluorodeoxyglycerol 3-phosphate was confirmed by comparison of chemical and physical properties of the compounds synthesized by this route, to the corresponding compounds prepared by ring opening of epifluorohydrin by aqueous acid, dibenzylphosphoric acid, or phosphoric acid, respectively. Nuclear magnetic resonance spectra of intermediates and of the final product are presented and analyzed. Racemic 1-fluorodeoxyglycerol 3-phosphate synthesized from glycerol is a substrate for rabbit muscle NAD-linked glycerol 3-phosphate dehydrogenase, and is indistinguishable in its kinetic behavior from the compound synthesized from epifluorohydrin. D-1-Fluorodeoxyglycerol 3-phosphate possesses no substrate activity with the enzyme, and inhibits the oxidation of L-glycerol 3-phosphate by the enzyme. The stereospecific synthetic route to D-1-fluorodeoxyglycerol 3-phosphate is readily applicable with slight modification to synthesis of the L enantiomorph. Availability of optically pure forms of D-and L-1-fluorodeoxyglycerol 3-phosphate will permit an examination of our suggestion that 1-fluoro analogs of glycerol 3-phosphate or dihydroxyacetone 3-phosphate or precursors that could generate them in vivo may be selectively toxic to cells lacking NAD-linked glycerol 3-phosphate dehydrogenase, which is a characteristic of many types of cancer cells.

AB - D-1-Fluoro-1-deoxyglycerol 3-phosphate was prepared starting from D-mannitol by the intermediate synthesis of D-2,3-isopropylideneglycerol, D-1-tosyl-2,3-isopropylideneglycerol, D-1-fluorodeoxy-2,3-isopropylideneglycerol, D-1-fluorodeoxyglycerol, and D-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester. The corresponding racemic compounds were also prepared starting from glycerol. The identity of DL-1-fluorodeoxyglycerol, DL-1-fluorodeoxyglycerol 3-phosphate dibenzyl ester, and DL-1-fluorodeoxyglycerol 3-phosphate was confirmed by comparison of chemical and physical properties of the compounds synthesized by this route, to the corresponding compounds prepared by ring opening of epifluorohydrin by aqueous acid, dibenzylphosphoric acid, or phosphoric acid, respectively. Nuclear magnetic resonance spectra of intermediates and of the final product are presented and analyzed. Racemic 1-fluorodeoxyglycerol 3-phosphate synthesized from glycerol is a substrate for rabbit muscle NAD-linked glycerol 3-phosphate dehydrogenase, and is indistinguishable in its kinetic behavior from the compound synthesized from epifluorohydrin. D-1-Fluorodeoxyglycerol 3-phosphate possesses no substrate activity with the enzyme, and inhibits the oxidation of L-glycerol 3-phosphate by the enzyme. The stereospecific synthetic route to D-1-fluorodeoxyglycerol 3-phosphate is readily applicable with slight modification to synthesis of the L enantiomorph. Availability of optically pure forms of D-and L-1-fluorodeoxyglycerol 3-phosphate will permit an examination of our suggestion that 1-fluoro analogs of glycerol 3-phosphate or dihydroxyacetone 3-phosphate or precursors that could generate them in vivo may be selectively toxic to cells lacking NAD-linked glycerol 3-phosphate dehydrogenase, which is a characteristic of many types of cancer cells.

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