Leroy B. Townsend

Phase I study of ftorafur, an analog of 5-fluorouracil

Ftorafur, a furanyl analog of 5‐fluorouracil (5‐FU), is reported to be five to six times less toxic and possibly more effective in cancer of the breast and colon than 5‐FU. The drug was synthesized, formulated, and utilized in toxicologic studies, and then in 24 patients with advanced incurable malignancies. When Ftorafur is given by intravenous push, it results in immediate flushing, dizziness, nausea, retching, and in some cases transient hypotension. These immediate side effects are largely eliminated by administering the drug slowly by infusion. In patients, 60 mg/kg of Ftorafur given i.v. daily for up to 10 days resulted in mild toxicity. However, 80 mg/kg given i.v. daily for 7 days resulted in severe toxicity, with nausea, vomiting, stomatitis, leukopenia, and thrombocytopenia. These studies confirm those of the Russian investigators as to toxicity and dosage, even with a different method of administration more convenient for therapy. Phase II studies are presently being carried out to compare the effectiveness of Ftorafur and 5‐FU.

Inhibition of hypoxanthine-guanine phosphoribosyl transferase.

Abstract The affinities of eighteen purines or purine analogs for human erythrocytic hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8; HGPRTase) were compared to assess the feasibility of obtaining active inhibitors of the enzyme. Three compounds appeared to inhibit the utilization of hypoxanthine by L5178Y cells in vitro due to inhibition of the enzyme rather than depletion of the intracellular 5-phosphoribosyl-1-pyrophosphate pool. The three competitive inhibitors and their affinity constants ( K i ) using 6-mercaptopurine as substrate were: 6-mercapto-9-(tetrahydro-2-furyl)-purine, 37 μM; 2,6-bis-(hydroxyamino)-9-β- d -ribofuranosyl-purine, 12 μM; and 6-iodo-9-(tetrahydro-2-furyl)-purine, 108 μM. The K In m for 6-mercaptopurine was 9 μM. Thus, the enzyme tolerates bulky substitution at N 9 . 6-Mercapto-9-(tetrahydro-2-furyl)-purine also potentiated the chemotherapeutic effect of azaserine, an inhibitor of de novo purine biosynthesis, in L5178Y ascites tumor-bearing mice. Four 2-substituted, oxazolo-[5, 4- d ]-pyrimidine-7-ones and 2-methylthiazolo-[5, 4- d ]-pyrimidine-7-one had K i values in the range of 84–173 μM. Consequently, isosteric substitution at N 9 may also be a fruitful and logical course to pursue in the design and synthesis of more potent inhibitors of this important enzyme.

The synthesis of α- and β-2′-deoxyselenoguanosine

The α- and β-anomers of 2′-deoxy-6-selenoguanosine have been prepared from 2-acetamido-6-chloro-9-(2-deoxy-3,5-di-O-p-toluoyl-α- and β-d-erythro-pentofuranosyl) purine. The structure of the individual anomers has been firmly established using ultraviolet and PMR spectroscopy. The potential anticancer activity of both anomers is discussed.

Formation of 3,5,5-trimethyl derivatives of dihydrouracil nucleosides by reaction with methylsulfinyl carbanion and methyl iodide.

Abstract 1. 5,6-Dihydrouracil nucleosides undergo selective reaction with methylsulfinyl carbanion and methyl iodide to form derivatives which are O-methylated in the sugar and methylated at positions 3,5,5 in the base. This behavior is unique to the 5,6-dihydropyrimidine system and provides a sensitive mass spectrometric test for the 5,6-dihydro moiety. 2. Structures of reaction products were determined by electron- and chemicalionization mass spectrometry, and by proton magnetic resonance.

Pyrazolopyrimidine nucleosides. Part IV. Synthesis and chemical reactivity of the C-nucleoside selenoformycin B and derivatives

The synthesis of 7-selenoxo-3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (2)(selenoformycin B) has been accomplished by a nucleophilic displacement of the chloro-group from 7-chloro-3-(β-D-ribofuranosyl)pyrazolo-[4,3-d]pyrimidine (1) with selenourea in ethanol at reflux temperature. Alkylation of (2) has furnished several 7-alkylseIeno-3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidines. A study on the relative reactivity of certain 7-substituted 3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidines and the corresponding 6-substituted 9-(β-D-ribofuranosyl)purines toward nucleophilic displacement is discussed. 7-Methoxy-3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (5) and the nebularine derivative 3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (3) have also been prepared. The stability of (2) towards basic and approximate physiological pH conditions is discussed.