Metabolism of folic acid. VI. Preparation of intermediary antimetabolites of folic acid

Slavík, K.; Slavíková, V.; Kolman, Z.

doi:10.1135/cccc19601929

Cited by 10 publications

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“…In summary, seven novel 2,4-diamino-5-deaza- 6,7,8,9-tetrahydropyrido[3,4-g]pteridine derivatives with a varied benzyl and a benzoyl substitution at the N7 position (3)(4)(5)(6)(7)(8)(9) were designed and synthesized as classical and nonclassical, conformationally restricted, linear, tricyclic 5-deaza antifolates to investigate the effect of the conformational restriction, of C6-C9 (τ 1 ) and C9-N10 (τ 2 ) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza MTX, with respect to the inhibitory potency against different pathogenic DHFR and antitumor activity. Biological studies indicated that this conformational modification was detrimental to DHFR inhibitory activity as well as to antitumor activity compared to MTX or 5-deaza MTX.…”

Section: Biological Evaluation and Discussionmentioning

confidence: 99%

“…Because of the frequent occurrence of tumor resistance and ineffectiveness against many solid tumors, extensive structural modifications of MTX have been reported to improve its antitumor spectrum of activity and to circumvent tumor resistance. [4][5][6][7] One area of structural modification that may afford increased biological activity is conformational restriction of flexible parts of a lead molecule.…”

Section: Introductionmentioning

confidence: 99%

“…

Seven novel 2,7,8,pteridine derivatives 3-9 with different benzyl and a benzoyl substitution at the N7 position were designed and synthesized, as classical and nonclassical, partially restricted, linear tricyclic 5-deaza antifolates. The purpose was to investigate the effect of conformational restriction of the C6-C9 (τ 1 ) and C9-N10 (τ 2 ) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza methotrexate (MTX) on the inhibitory potency against dihydrofolate reductase (DHFR) from different sources and on antitumor activity.

…”

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confidence: 99%

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Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

et al. 2002

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Seven novel 2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridine derivatives 3-9 with different benzyl and a benzoyl substitution at the N7 position were designed and synthesized, as classical and nonclassical, partially restricted, linear tricyclic 5-deaza antifolates. The purpose was to investigate the effect of conformational restriction of the C6-C9 (tau(1)) and C9-N10 (tau(2)) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza methotrexate (MTX) on the inhibitory potency against dihydrofolate reductase (DHFR) from different sources and on antitumor activity. The synthetic methodology for most of the target compounds was a concise five-step total synthesis to construct the tricyclic nucleus, 2,4-diamino-5-deaza-7H-6,7,8,9-tetrahydropyrido[3,4-g]pteridine (23), followed by regioselective alkylation of the N7 nitrogen. Biological results indicated that this partial conformational modification for the classical analogue N-[4-[(2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridin-7-yl)methyl]benzoyl]-L-glutamic acid 3 was detrimental to DHFR inhibitory activity as well as to antitumor activity compared to MTX or 5-deaza MTX. However, the classical analogue 3 was a better substrate for folypolyglutamate synthetase (FPGS) than MTX. These results show that a classical 5-deaza folate partially restricted via a bridge between the N10 and C7 positions retains FPGS substrate activity and that the antitumor activity of classical tricyclic analogues such as 3 would be influenced by FPGS levels in tumor systems. Interestingly, the nonclassical analogues 4-9 showed moderate to good selectivity against DHFR from pathogenic microbes compared to recombinant human DHFR. These results support the idea that removal of the 5-methyl group of piritrexim along with restriction of tau(1) and tau(2) can translate into selectivity for DHFR from pathogens.

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Section: Biological Evaluation and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

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“…Sepharose 4B was obtained from Pharmacia, cyanogen bromide from Schuchardt, w-alkylenediamines from Lachema, deoxyuridine 5'-monophosphate from Koch-Light. Tetrahydrofolate was prepared from folic acid by catalytic hydrogenation in acetic acid with subsequent precipitation of the product with ether (Slavik et al, 1960). Tetrahydromethotrexate was prepared by a similar procedure from methotrexate Lederle (Slavik et al, 1960).…”

Section: Methodsmentioning

confidence: 99%

“…Tetrahydrofolate was prepared from folic acid by catalytic hydrogenation in acetic acid with subsequent precipitation of the product with ether (Slavik et al, 1960). Tetrahydromethotrexate was prepared by a similar procedure from methotrexate Lederle (Slavik et al, 1960). The material contained about 70% of the mixture of two diastereomers of tetrahydromethotrexate, 20% dihydromethotrexate, and a small amount of p-methylaminobenzoyl glutamate (as shown by gradient elution on DEAE-cellulose column).…”

Section: Methodsmentioning

confidence: 99%

Purification of thymidylate synthetase from enzyme-poor sources by affinity chromatography

Slavík¹,

Rode²,

Slavíková³

1976

Biochemistry

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The adsorption of thymidylate synthetase from Escherichia coli B to aminoalkyl-Sepharose with the increasing length of carbon chain (2--6 carbon atoms) was investigated. A correlation was found between the chain length and adsorption effectiveness, increasing from the two- to the six-carbon chain. A hydrophobic chromatography of the enzyme on aminobutyl-Sepharose gave about 20-fold purification. A new affinity chromatography carrier was synthesized containing tetrahydromethotrexate linked to aminoethyl-Sepharose via its carboxylic groups. The carrier adsorbed the enzyme from the crude preparation only in the presence of deoxyuridine 5'-monophosphate (dUMP) in a concentration of 2 X 10(-5) M. The specifically adsorbed thymidylate synthetase was eluted with sacharose-containing buffers in which dUMP was omitted. The purification procedure was applied to a crude thymidylate synthetase preparation from resting E. coli, calf thymus, Sarcoma 180, and Gardner lymphosarcoma. The purified enzyme from all mentioned sources showed one protein band on disc electrophoresis corresponding to enzymatic activity. The formation of a reversible noncovalent complex enzyme-tetrahydromethotrexate-dUMP on the affinity column is supposed.

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Folsäure und Folat-Enzyme.

Jaenicke¹,

Kutzbach²

1963

Progress in the Chemistry of Organic Natural Products/Progrès Dans La Chimie Des Substances Organiques Naturelles

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Metabolism of folic acid. VI. Preparation of intermediary antimetabolites of folic acid

Cited by 10 publications

References 0 publications

Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

Purification of thymidylate synthetase from enzyme-poor sources by affinity chromatography

Folsäure und Folat-Enzyme.

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