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Screening Data from Selected in Vitro Enzymatic Systems

II. Compounds Specifically Selected for the Dehydrogenase Inhibition Screens¹

Four dehydrogenase reactions measured in vitro were used to detect compounds of potential use in the chemotherapy of cancer. Inhibitors of lactate dehydrogenase and L-glycerol-3-phosphate dehydrogenase were sought, based on the proposal that inhibition of these enzymes might be more deleterious to malignant than normal tissues. Some compounds were also tested for inhibition of malate and alcohol dehydrogenase, primarily to exclude nonspecific dehydrogenase inhibitors. Results are presented on 259 compounds which were selected for possible structural relationships to substrates or known inhibitors, as well as for diversity of structural types. In an attempt to improve the detection of dehydrogenase inhibitors, 2 modifications of the standard protocol were investigated to select irreversible inhibitors and compounds that might form inhibitory products in vivo. Over 20% of the reported compounds significantly inhibited 1 or more of the dehydrogenases.

¹ Supported by contract PH-43-64-883 from the Cancer Chemotherapy National Service Center, National Cancer Institute, USPHS.

² Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, New Jersey, and West Point, Pennsylvania.

³ Present address: Department of Pharmacology, Hahnemann Medical College, Philadelphia, Pennsylvania.

⁴ Present address: Department of Biological Chemistry, Hahnemann Medical College, Philadelphia, Pennsylvania.