The synthesis of t w o new pteridine-7-spirocyclopropanes that are time-dependent irreversible inhibitors of dihydrofolate reductase is described. Several related compounds including a cyclopropyl substituted quinoxaline and 2-aminopteridine-4(3H),6(5H) -dione were also prepared but these compounds were not found to be time-dependent inhibitors. The inhibitors were assessed using several dihydrofolate reductases, Escherichia cob RT/39, two mutants of the E. coli enzyme, L actobacillus casei, and chicken liver. Activity was found against all enzymes tested but most strongly against E. coIi wild type enzyme.

A new synthetic route to 5,8-dideazaisofolic acid (IAHQ) is described which precludes the possibility of contamination due to its 4-amino counterpart 5,8-dideazaisoaminopterin. Substitution of D-glutamic acid in this synthetic scheme gave D-IAHQ. The 9-formyl, 9-methyl, 5-methyl, and 5,9-dimethyl modifications of IAHQ were also prepared. These compounds, together with several structurally related or isomeric analogues, were studied for inhibitory effects upon the growth of four human gastrointestinal adenocarcinoma cell lines in vitro. In general, the compounds having a normal folate configuration at positions 9 and 10 are more active than their reversed bridge isomers. The lack of antitumor activity of D-IAHQ provides indirect evidence concerning the mechanism of action of IAHQ.

Additions and Corrections ce,a-Bis(2-hydroxy-6-isopropyltropon-3-yl)toluenes (13g-i) were prepared in the same manner. a,a-Bis(7-hydroxy-5-isopropyltropon-2-yl)-2-methoxytoluene (13g): mp 148-151 °C (from MeOH~CH2Cl2); yield 8%; NMR (CDC13) 3.76 (s, 3 H, OCH3); MS, m/e 446 (M+). Anal.(C28H30O5) C, H. a,a-Bis(7-hydroxy-5-isopropyltropon-2-yl)-3-methoxytoluene (13h): mp 192-194 °C (from MeOH-CH2Cl2); yield 27%; NMR (CDC13) 3.76 (s, 3 H, OCH3); MS, m/e 446 (M+). Anal. (C28H30O6) C, H.

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Auf den im Formelschema beschriebenen Wegen werden die Titelverbindung (VIIa) sowie die Analoga (VIIb), (VIII) und (IX) dargestellt.