Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin

Dawson, Marcia I.; Okrongly, David; Hobbs, Peter D.; Barrueco, José; Sirotnak, F. M.

doi:10.1002/jps.2600760810

Cited by 11 publications

(4 citation statements)

References 12 publications

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“…Moreover there were also more byproducts, possibly resulting from cleavage of the 4-amino group and rupture of the pyrimidine ring. Another method of ester cleavage involving the use of cyanide ion as a nucleophile was abandoned when it was found to lead to a complex mixture of products, possibly reflecting the known susceptibility of pteridines to cyanide attack at the C-7 position . Other strong nucleophiles were not investigated.…”

Section: Chemistrymentioning

confidence: 99%

“…The solution was applied onto a column of silica gel (flash grade, 20 g, 22 × 1.5 cm), which had been prepared with 85:15:1 CHCl 3-MeOH-28% NH4OH and was eluted with the same solvent. Homogeneous fractions (TLC: Rf 0.25, silica gel 9:1 CHCl3-MeOH) were pooled and evaporated to obtain 28 as a pale-yellow solid (102 mg), thus bringing the total yield to 160 mg (54% (33). Metallic Na (14 mg, 0.6 mmol) was added to MeOH (2.5 mL) and the solution was added to a solution of guanidine hydrochloride (57 mg, 0.6 mmol) in MeOH (15 mL).…”

Section: Methyl 2-l-[n-(4-formylbenzoyl)amino]-5-phthalimidopentanoat...mentioning

confidence: 99%

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Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

et al. 2000

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Seven N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-o rnithine (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. In growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC(50) values of analogues in which N(10) was replaced by CH(2) and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC(50) = 4.4 +/- 1.0 nM) or 2 (IC(50) = 1.5 +/- 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC(50) = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC(50) of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO(2)Me group at the 10-position had an IC(50) of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC(50) of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH(2))(3) side chain was replaced by slightly longer CH(2)SCH(2) and (CH(2))(2)SCH(2) groups gave IC(50) values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC(50) values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9, 10-bridge are well-tolerated and can even increase potency.

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Section: Chemistrymentioning

confidence: 99%

Section: Methyl 2-l-[n-(4-formylbenzoyl)amino]-5-phthalimidopentanoat...mentioning

confidence: 99%

Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

et al. 2000

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“…3 H-Methotrexate (specific activity, 8.2 Ci/mmol) was obtained from Amersham Life Science (Cleveland, Ohio). 7-Hydroxymethotrexate was synthesized according to the method of Dawson et al 15 The nuclear magnetic resonance spectra obtained from the product of this synthesis matched published data for 7-hydroxymethotrexate, and purity was more than 97% according to HPLC and comparison with published extinction coefficients.…”

Section: Methodsmentioning

confidence: 71%

Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease

Egan

Sandborn

Mays

et al. 1999

Clinical Pharmacology & Therapeutics

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Subcutaneous methotrexate was well absorbed and distributed to the site of the lesions in patients with inflammatory bowel disease. Methotrexate was concentrated intracellularly in blood and in the rectum. The methotrexate concentration in the rectal mucosa remained within a pharmacologically active range throughout the dosing interval. The findings represent a pharmacologic explanation for the sustained efficacy of weekly methotrexate therapy.

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“…D), DAMPA, folic acid (FA), and calcium folinate (CF) were purchased from Sigma‐Aldrich (Tokyo, Japan). 7‐OH‐MTX was synthesized according to the procedure described by Dawson et al ().…”

Section: Methodsmentioning

confidence: 99%

Simple and sensitive HPLC method for the fluorometric determination of methotrexate and its major metabolites in human plasma by post‐column photochemical reaction

Uchiyama

Matsumoto

et al. 2011

Biomedical Chromatography

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A simple and sensitive HPLC method has been developed for the determination of methotrexate (MTX) and its major metabolites, 7-hydroxymethotrexate (7-OH-MTX) and 2,4-diamino-N(10-) methylpteroic acid (DAMPA), in human plasma. After deproteinization of the plasma with 5% aqueous acetonitrile solution containing 5% trichloroacetic acid, MTX, 7-OH-MTX, DAMPA and 2,4-diaminopteroic acid (DAPA) as an internal standard were separated on a reversed-phase column, and the eluent was subsequently irradiated with UV light (245 nm), producing fluorescent photolytic degradation products. The analytes were then detected spectrofluorometrically at 452 nm with excitation at 368 nm. The extraction efficiencies of MTX, 7-OH-MTX and DAMPA from plasma at 100 pmol/mL were 81.5±5.4, 82.5±5.3 and 56.2±7.0%, respectively. The limits of quantification for MTX, 7-OH-MTX and DAMPA in plasma were 5 pmol (2.3 ng), 0.8 pmol (0.38 ng) and 10 pmol (3.4 ng)/mL, respectively. The within- and between-day variations for MTX, 7-OH-MTX and DAMPA were reliable (each was lower than 6.3%). This method was also used to monitor the concentrations of MTX and its metabolites in a patient on MTX therapy.

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Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin

Cited by 11 publications

References 12 publications

Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease

Simple and sensitive HPLC method for the fluorometric determination of methotrexate and its major metabolites in human plasma by post‐column photochemical reaction

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Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin

Cited by 11 publications

References 12 publications

Analogues of the Potent Nonpolyglutamatable Antifolate Nα-(4-Amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

Analogues of the Potent Nonpolyglutamatable Antifolate Nα-(4-Amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease

Simple and sensitive HPLC method for the fluorometric determination of methotrexate and its major metabolites in human plasma by post‐column photochemical reaction

Contact Info

Product

Resources

About

Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity

Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge: Synthesis and in Vitro Antitumor Activity