Improved synthesis and antitumor evaluation of 5,8-dideazaisofolic acid and closely related analogs

Hynes, John B.; Yang, Y. C. S.; McGill, J.; Harmon, Shona; Washtien, Wendy L.

doi:10.1021/jm00368a023

Cited by 30 publications

(4 citation statements)

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“…Di- tert -butyl l -α-aminoadipate ( 5 ) was coupled to 4-formylbenzoic acid using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N,N -diisopropylethylamine, affording 8 . Compounds 6 and 7 were synthesized in a similar manner starting from the commercially available di- tert -butyl esters of l - and d -glutamic acid hydrochloride, respectively. The aldehydes were oxidized immediately after purification to the corresponding carboxylic acids 9 − 11 , using sodium chlorite in tert -butyl alcohol with 2-methyl-2-butene as scavenger. − 2,4-Diaminoquinazoline-6-methanol was subjected to 30% hydrobromic acid in glacial acetic acid, providing compound 12 …”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Dihydrofolate Reductase Inhibitors Encompassing a Bridging Ester Group. Evaluation in a Mouse Colitis Model

et al. 2003

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Crohn's disease is a chronic inflammatory bowel disease characterized by inflammation of both the small and large intestines. Methotrexate (MTX), a classical dihydrofolate reductase (DHFR) inhibitor, has been used as a therapeutic agent in the treatment of patients with Crohn's disease in recent years. We sought to develop antifolates similar in structure to MTX that would be effective in reducing inflammation in a mouse disease model of colitis. Four classical DHFR inhibitors encompassing ester bridges in the central parts of the molecules were synthesized. These antifolates were efficient inhibitors of the DHFR enzyme derived from rat. They were also tested in vitro for their ability to inhibit induced proliferation of lymphocytes from mouse spleen. Inhibition of cell proliferation was achieved only in the micromolar range, whereas MTX was effective at low nanomolar concentrations. One of the DHFR inhibitors (1), with an IC(50) value for rlDHFR approximately 8 times higher than that of methotrexate, was selected for in vivo experiments in an experimental colitis model in mice. This compound demonstrated a clear antiinflammatory effect after topical administration, comparable to the effect achieved with the glucocorticoid budesonide. Three parameters were evaluated in this model: myeloperoxidase activity, colon weight, and inflammation scoring. A favorable in vivo effect of compound 1 (15 mg/(kg.day)) was observed in all three inflammatory parameters. However, the results cannot be explained fully by DHFR inhibition or by inhibition of lymphocyte cell proliferation, suggesting that other yet unidentified mechanisms enable reduction of inflammation in the colitis model. The mechanism of action of methotrexate analogues encompassing a bridging ester group is not well understood in vivo but seems to lend itself well to further development of similar compounds.

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Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Dihydrofolate Reductase Inhibitors Encompassing a Bridging Ester Group. Evaluation in a Mouse Colitis Model

et al. 2003

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“…Diethyl AT-[4-[[[3,4-Dihydro-4-oxo-3-[(pivaloyloxy)methyl]-6-quinazolinyl]methyl]thio]benzoyl]-L-glutamate (10). A solution of tetraethyl 4,4'-dithiobis(benzoyl-L-glutamate) (0.24 g, 0.36 mmol) in 5 mL of EtOH was treated with 0.27 g (0.71 mmol) of NaBH4.…”

Section: Methodsmentioning

confidence: 99%

“…After removal of the solvent at reduced pressure, the resulting oil was dissolved in ca. 10 mL of CHC13 and slurried with silica gel, and the mixture was applied to a silica gel column (26 X 2.8 cm). Elution with CHCl3-MeOH, 99:1, removal of the solvent under vacuum, and drying under vacuum over P205 at 65 °C gave 2.55 g (67%) of 11: mp 107.5-113.5 °C; TLC R¡0.17 (Whatman KC18F reverse phase, Me0H-H20,8:2); NMR (CDC13) 1.18 [s, 9, C(CH3)3], 3.87 (s, 3, CH3), 5.22 (s, 2, CH20), 5.94 (s, 2, COOCH2), 6.98 (d, 2, 3', 5', J0 = 8.88 Hz), 7.77 (d, 1, Hs, Ja7 = 8.37 Hz), 7.85 (dd, 1, H7, Jls = 8.37 Hz, J7a = 1.95 Hz), 7.98 (d, 2, 2', 6', J0 = 8.85 Hz), 8.33 (s, 1, H2), 8.37 (d, 1, H5, Ji7 = 1.71 Hz).…”

Section: Methodsmentioning

confidence: 99%

Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts

Hynes

Patil²,

Hagan³

et al. 1989

J. Med. Chem.

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Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.

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“…However, many of these 5,8-dideazaaminopterin analogues mechanism of action of IAHQ involves its intracellular conversion to poly-y-L-glutamyl metabolites, which are significantly more potent as inhibitors of TS, particularly in the presence of high concentrations of 2'-deoxyuridine monophosphate, dUMP, which accumulate due to the inhibition of TS.8 Although numerous analogues of IAHQ were prepared, such as lb-f, none has demonstrated superior cytotoxicity toward human gastrointestinal tumor cells in vitro. 9 It was of interest, therefore, to prepare the bridge-reversed isomer of CB3717, 9-propargyl-5,8-dideazaisofolic acid, 4b, as well as related 9-substituted analogues. Each of the new compounds synthesized as well as members of a large series of related analogues was evaluated for inhibition of L1210 leukemia TS as well as human tumor DHFR in an effort to develop new structure-activity patterns to facilitate the design of more selective inhibitors of TS.…”

mentioning

confidence: 99%

Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogs of folic acid and aminopterin

Hynes¹,

Patil²,

Tomazic³

et al. 1988

J. Med. Chem.

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A series of 5,8-dideaza analogues of folic acid, isofolic acid, aminopterin, and isoaminopterin were evaluated for inhibition of thymidylate synthase, TS, from mouse L1210 leukemia cells with 10-propargyl-5,8-dideazafolic acid, CB3717, 4a, as the reference inhibitor. These compounds were also tested as inhibitors of human dihydrofolate reductase, DHFR, obtained from WIL2 cells. None of the analogues studied were as potent as 4a toward TS; however, 9-methyl-5,8-dideazaisoaminopterin, 6d, was only 2.5-fold less effective. Compound 4a was prepared by direct alkylation of the di-tert-butyl ester of 5,8-dideazafolic acid followed by hydrolysis of the resulting diethyl ester, which resulted from concomitant transesterification. It was found to be identical with a sample of 4a prepared by earlier methodology by using a variety of spectroscopic techniques. Its isomer, 9-propargyl-5,8-dideazaisofolic acid, 4b, which was synthesized by an analogous approach, was found to be dramatically less inhibitory toward TS than 4a. Each of the 2,4-diamino derivatives, including those possessing an allyl or propargyl group at N9, was an excellent inhibitor of DHFR, having a level of potency similar to that of methotrexate, MTX. However, many of these 5,8-dideazaaminopterin analogues were far more inhibitory toward TS than MTX.

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Improved synthesis and antitumor evaluation of 5,8-dideazaisofolic acid and closely related analogs

Cited by 30 publications

References 0 publications

Design and Synthesis of Dihydrofolate Reductase Inhibitors Encompassing a Bridging Ester Group. Evaluation in a Mouse Colitis Model

Design and Synthesis of Dihydrofolate Reductase Inhibitors Encompassing a Bridging Ester Group. Evaluation in a Mouse Colitis Model

Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts

Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogs of folic acid and aminopterin

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