Synthesis of 5,10‐dideazaminopterin

Abstract

The synthesis of 5,lO-dideazaaminopterin by two independent routes is described. Condensation of the piperidine enamine of 4-p-carbomethoxyphenylbutyraldehyde (4) with ethoxymethylenemalononitrile followed by treatment of the resultant arylethylenaminomalononitrile (5) with methanolic ammonia produced Z-amino-3-cyano-5-p-carbomethoxyphenethylpyridine (6). Cyclization of the aminocyanopyridine with guanidine afforded 4-amino-4-deoxy-5,10-dideazapteroic acid (8). Coupling of the pteroate intermediate with glutamate yielded the target 5,lO-dideazaaminopterin (10).Alternatively, reduction of 2,4-diamino-6-formyl-5-deazapteridine (11) with sodium borohydride gave the 6-hydroxymethyl compound 12. Conversion to the bromide was followed by alkylation of dimethyl homoterephthalate to afford methyl 4-amino-4-deoxy-lO-carbomethoxy-5,1O-dideazapteroate (14). Decarboxylation with ester cleavage (sodium cyanide in dimethyl sulfoxide at 180O) also gave the diaminopteroic acid (8).5,lO-dideazaaminopterin (10) was an effective growth inhibitorof folate dependent bacteria, S.fuechrn and L. casei.

Potential anticancer agents. 5-(N-Substituted-aminocarbonyl)- and 5-(N-substituted-aminothiocarbonyl)-5,6,7,8-tetrahydrofolic acids

“…Both THF and its 10-substituted derivatives undergo decomposition readily, whereas, 5formyl-THF is stable under neutral and alkaline conditions.10 Products 4-15 were dissolved in 0.01 N NaOH, and these solutions were used in the determination of the UV absorption spectra in 0.1 N HC1, pH 7 buffer, and 0.1 N NaOH (Table I). Substitution at N-5 of THF was indicated by stable UV maxima in the 280-290-nm region, which is similar to that observed for 5-formyl-THF (Xmax, pH 7, 287 nm).lc Previously, another method was developed to differentiate between substitution at N-5 and N-10.7 The NMR spectra of DMSO-d6 or D20 solutions of derivatives of THE substituted at N-5 (e.g., CO) exhibited peaks for the phenylene protons in the range 6.5-7.0 and 7.5-7.9 ppm, which is consistent with the chemical shifts observed for [4][5][6][7][8][9][10][11][12][13][14][15]. In contrast, THE derivatives substituted with an unsaturated group (e.g., CO) at N-10 gave ranges of 7.…”

“…A. [5][6]hexyl]amino]-carbonyI]-5,6,7,8-tetrahydrofolic Acid (7). A solution of 5.6.7.8-tetrahydrofolic acid (2.07 g, 4.07 mmol)7,10 and Na0Ac-3H20 (2.04 g, 15.0 mmol) in deoxygenated H20 (130 mL) was treated with 2b (1.05 g, 5.29 mmol), stirred vigorously under N2 for 4 h, treated with CaCl2 (859 mg, 7.74 mmol), adjusted to pH 7.5 with 10% NaOH, and diluted with EtOH (600 mL).…”

Heterocycles with 7 and 8π electrons. Models for flavin and pteridine intermediates and candidates for novel inorganic rings

“…Figure 9). The replacement of CH by N is not only useful in order to understand the function of each individual center; supported by perturbation calculations [223], it can also provide guidelines for a systematic design of "a~a ~-znd ~deaza~-modified coenzymes which have recently been the focus of intense research and which often exhibit markedly different reactivity and physiological effects [28,33,[166][167][168][169].…”

Synthesis of Novel Pyrido[1,2-<i>a</i>]pyrimidine-3-carboxamide Derivatives and Their Anticancer Activity

“…Last few decades of research on pyrido pyrimidine derivatives revealed that, they had wide range of therapeutic applications such as antitumor, [3][4][5][6] antibacterial, [7][8][9] antifungal, [10][11][12][13] anti-inflammatory, 14) anti-allergic, 15) antidiabetic, 16) antiviral, [17][18][19] anti-herpes 20) and calcium channel blocking activity. 21,22) Many pyrimidine derivatives are used for thyroid drugs and leukemia.…”