Synthesis of 1-Halo Analogs of DL-glycerol 3-phosphate and their effects on glycerol phosphate dehydrogenase

Thomas P Fondy, Gurdev S. Ghangas, Michael J. Reza

Research output: Contribution to journalArticle

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Abstract

1-Fluoro, 1-chloro, and 1-bromo analogs of DL-glycerol-3-P have been synthesized from the corresponding epihalohydrins with either phosphoric acid or dibenzylphosphoric acid. The 1-halodeoxyglycerol phosphates so obtained were demonstrated to be analogs of glycerol-3-P rather than glycerol-2-P by nuclear magnetic resonance spectra and by synthesis from 1-halodeoxyglycerol and dibenzylphosphorochloridate. 1-Fluorodeoxy-DL-glycerol-3-P is a substrate for rabbit muscle nicotinamideadenine dinucleotide (NAD)-linked glycerol-3-P-dehydrogenase with an Km (app) of 8 mM at pH 7.5 and 6.5 mM at pH 9.0. 1-Chlorodeoxy- and 1-bromodeoxy-DL-glycerol-3-P do not appear to be substrates for glycerol 3-phosphate dehydrogenase unless 0.1 M hydrazine is present. All three halo analogs are substrates for calf intestine alkaline phosphatase. None of the three halo analogs of DL-glycerol-3-P appears to be an irreversible inhibitor of NAD-linked glycerol-3-P-dehydrogenase, at either pH 7.5 or 9.0, although nonspecific organic phosphate incorporation is observed with the chloro and bromo analogs, particularly at pH 9.0. We suggest that the 1-fluoro analogs of L-glycerol-3-P or of dihydroxyacetone-3-P or derivatives of them may be useful as agents selectively toxic to cells lacking NAD-linked glycerol-3-P-dehydrogenase, which is a characteristic of many rapidly growing cancer cells.

Original languageEnglish (US)
Pages (from-to)3272-3280
Number of pages9
JournalBiochemistry
Volume9
Issue number16
StatePublished - 1970
Externally publishedYes

Fingerprint

glycerol dehydrogenase
Glycerol
Oxidoreductases
Phosphates
hydrazine
Substrates
Dihydroxyacetone
alpha-glycerophosphoric acid
Glycerolphosphate Dehydrogenase
Organophosphates
Poisons

ASJC Scopus subject areas

  • Biochemistry

Cite this

Synthesis of 1-Halo Analogs of DL-glycerol 3-phosphate and their effects on glycerol phosphate dehydrogenase. / Fondy, Thomas P; Ghangas, Gurdev S.; Reza, Michael J.

In: Biochemistry, Vol. 9, No. 16, 1970, p. 3272-3280.

Research output: Contribution to journalArticle

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abstract = "1-Fluoro, 1-chloro, and 1-bromo analogs of DL-glycerol-3-P have been synthesized from the corresponding epihalohydrins with either phosphoric acid or dibenzylphosphoric acid. The 1-halodeoxyglycerol phosphates so obtained were demonstrated to be analogs of glycerol-3-P rather than glycerol-2-P by nuclear magnetic resonance spectra and by synthesis from 1-halodeoxyglycerol and dibenzylphosphorochloridate. 1-Fluorodeoxy-DL-glycerol-3-P is a substrate for rabbit muscle nicotinamideadenine dinucleotide (NAD)-linked glycerol-3-P-dehydrogenase with an Km (app) of 8 mM at pH 7.5 and 6.5 mM at pH 9.0. 1-Chlorodeoxy- and 1-bromodeoxy-DL-glycerol-3-P do not appear to be substrates for glycerol 3-phosphate dehydrogenase unless 0.1 M hydrazine is present. All three halo analogs are substrates for calf intestine alkaline phosphatase. None of the three halo analogs of DL-glycerol-3-P appears to be an irreversible inhibitor of NAD-linked glycerol-3-P-dehydrogenase, at either pH 7.5 or 9.0, although nonspecific organic phosphate incorporation is observed with the chloro and bromo analogs, particularly at pH 9.0. We suggest that the 1-fluoro analogs of L-glycerol-3-P or of dihydroxyacetone-3-P or derivatives of them may be useful as agents selectively toxic to cells lacking NAD-linked glycerol-3-P-dehydrogenase, which is a characteristic of many rapidly growing cancer cells.",
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N2 - 1-Fluoro, 1-chloro, and 1-bromo analogs of DL-glycerol-3-P have been synthesized from the corresponding epihalohydrins with either phosphoric acid or dibenzylphosphoric acid. The 1-halodeoxyglycerol phosphates so obtained were demonstrated to be analogs of glycerol-3-P rather than glycerol-2-P by nuclear magnetic resonance spectra and by synthesis from 1-halodeoxyglycerol and dibenzylphosphorochloridate. 1-Fluorodeoxy-DL-glycerol-3-P is a substrate for rabbit muscle nicotinamideadenine dinucleotide (NAD)-linked glycerol-3-P-dehydrogenase with an Km (app) of 8 mM at pH 7.5 and 6.5 mM at pH 9.0. 1-Chlorodeoxy- and 1-bromodeoxy-DL-glycerol-3-P do not appear to be substrates for glycerol 3-phosphate dehydrogenase unless 0.1 M hydrazine is present. All three halo analogs are substrates for calf intestine alkaline phosphatase. None of the three halo analogs of DL-glycerol-3-P appears to be an irreversible inhibitor of NAD-linked glycerol-3-P-dehydrogenase, at either pH 7.5 or 9.0, although nonspecific organic phosphate incorporation is observed with the chloro and bromo analogs, particularly at pH 9.0. We suggest that the 1-fluoro analogs of L-glycerol-3-P or of dihydroxyacetone-3-P or derivatives of them may be useful as agents selectively toxic to cells lacking NAD-linked glycerol-3-P-dehydrogenase, which is a characteristic of many rapidly growing cancer cells.

AB - 1-Fluoro, 1-chloro, and 1-bromo analogs of DL-glycerol-3-P have been synthesized from the corresponding epihalohydrins with either phosphoric acid or dibenzylphosphoric acid. The 1-halodeoxyglycerol phosphates so obtained were demonstrated to be analogs of glycerol-3-P rather than glycerol-2-P by nuclear magnetic resonance spectra and by synthesis from 1-halodeoxyglycerol and dibenzylphosphorochloridate. 1-Fluorodeoxy-DL-glycerol-3-P is a substrate for rabbit muscle nicotinamideadenine dinucleotide (NAD)-linked glycerol-3-P-dehydrogenase with an Km (app) of 8 mM at pH 7.5 and 6.5 mM at pH 9.0. 1-Chlorodeoxy- and 1-bromodeoxy-DL-glycerol-3-P do not appear to be substrates for glycerol 3-phosphate dehydrogenase unless 0.1 M hydrazine is present. All three halo analogs are substrates for calf intestine alkaline phosphatase. None of the three halo analogs of DL-glycerol-3-P appears to be an irreversible inhibitor of NAD-linked glycerol-3-P-dehydrogenase, at either pH 7.5 or 9.0, although nonspecific organic phosphate incorporation is observed with the chloro and bromo analogs, particularly at pH 9.0. We suggest that the 1-fluoro analogs of L-glycerol-3-P or of dihydroxyacetone-3-P or derivatives of them may be useful as agents selectively toxic to cells lacking NAD-linked glycerol-3-P-dehydrogenase, which is a characteristic of many rapidly growing cancer cells.

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