Synthesis of quinazoline analogs of isofolic acid

Abstract

Four quinazoline analogs of isofolic acid were synthesized including 5-methyl-5,8-deazaisofolic acid (8a), 5,8-deazaisofolic acid (8c), as well as their 4-NH2 counterparts 8b and 8d. None of these showed significant activity against L1210 leukemia in mice at dose levels where amethopterin provided significant prolongation in survival.

Effects of Three New Folate Antagonists on Human Breast Adenocarcinoma Cells in vitro and on Immune Responses in vivo

“…Hamsters were used in this study to investigate the effects of these compounds on the immune repsonse in vi vo. The reasons for using hamsters are two-fold: (1) it enabled us to perform a time study (2,6,8,12 days) of the effects of the compounds on hamsters postinjec tion, and (2) we have standardized assays for immune parameter studies in hamsters [13]. Our data suggest that all three com pounds suppressed both NK activity and mitogen-induced lymphocyte prolifera tion when injected into hamsters.…”

“…A considerably higher yield was obtained with this modification. 10-OXA-AHQ and 5-CHr IAHQ were synthesized by the methods described by Oatiset al [9] and Hynes et al [6], respectively. .…”

“…5-Methyl-5,8-dideazaisofolic acid (5-CH3-IAHQ) ( fig. lc), a closely related analogue of IAHQ, was synthesized earlier and was found to be inactive against L-1210 leu kemia in mice [6].…”

Benzo[f]quinazoline Inhibitors of Thymidylate Synthase: Methyleneamino-Linked Aroylglutamate Derivatives

“…The residue was purified with silica gel chromatography eluting with methylene chloride-THF (5: 1). Fractions containing product were concentrated in vacuo to a thick paste, and the solid was suspended in a small volume of diethyl ether, filtered under nitrogen, and dried under vacuum to give 9c as a white solid (2.3 g, 46%): NMR (DMSO-d6,300 MHz) 1.15 (t, J = 7 Hz, 3H, ester CH3), 1.18 (t, J = 7 Hz, 3H, ester CHS), 1.87-2.13 (m, 2H, Glu CH2), 2.38 (t, J = 7 Hz, 2H, Glu CH2), 2.43 (s, 3H, C3-CH3), 4.02 (q, J = 7 Hz, 2H, ester CH2), 4.09 (q, J = 7 Hz, 2H, ester CH2), 4.34-4.44 (m, 1H, Glu CH), 4.57 (d, J = 6 Hz, 2H, C9-CH2), 6.39 (dd, J = 15, 2 Hz, 1H, Ar), 6.53 (dd, J = 9,2 Hz, 1H, Ar), 7.30 (t, J = 6 Hz, 1H, ArNH), 7.44 (dd, =7 = 9,9 Hz, 1H, Ar), 7.60 (d, =7 = 9 Hz, 1H, Ar), 7.61 (dd, «7 = 8, 2 Hz, 1H, Ar), 7.88 (dd, =7 = 7, 5 Hz, 1H, Glu NH), 8.01 (d, =7 = 8 Hz, 1H, Ar), 8.22 (d, <7 = 9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.53 A solution of 9c (2.3 g, 4.1 mmol) in ethanol (25 mL) and 0.2 N NaOH (100 mL) was stirred under nitrogen at room temperature for 3 h. The solution was adjusted to pH 7 with 1 N HC1 and reduced in volume under vacuum to remove the ethanol. The product was precipitated by acidifying the solution with 1NHC1 to pH 3 with stirring under nitrogen.…”

“…The product was precipitated by acidifying the solution with 1NHC1 to pH 3 with stirring under nitrogen. The suspension was stirred 15 min, filtered under nitrogen, washed with water, pressed with a sheet of latex to remove excess water, and dried under vacuum to give 3c as a white solid (2.1 g, 93 %): XH NMR (DMSO-d6,300 MHz) 1.82-2.12 (m, 2H, Glu CH2), 2.29 (t, J = 7 Hz, 2H, Glu CH2), 2.43 (s, 3H, C3-CH3), 4.32-4.42 (m, 1H, Glu CH), 4.57 (d, «7 = 6Hz, 2H, C9-CH2),6.39 (dd,,7=15,2 Hz, 1H, Ar), 6.53 (dd, =7=9,2 Hz, 1H, Ar), 7.30 (t, =7 = 6 Hz, 1H, ArNH), 7.47 (dd, J = 9,9 Hz, 1H, Ar), 7.59 (d, J = 9 Hz, 1H, Ar), 7.61 (dd, =7=8, 2 Hz, 1H, Ar), 7.73 (t, =7 = 7 Hz, 1H, Glu NH), 8.01 (d,=7=8 Hz, 1H, Ar), 8.22 (d, =7 = 9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.42 (br s, 2H, C02H'), 12.53 (s, 1H, N2H). Anal.…”