Synthesis of 1-Halo Analogs of DL-Glycerol 3-Phosphate and Their Effects on Glycerol Phosphate Dehydrogenase

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 nicotinamide-adenine dinucleotide (NAD)-linked glycerol-3-P-dehydro-genase with an Km (app) of 8 mM at pH 7.5 and 6.5 mvt 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 dihydroxy-acetone-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.