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Carsten Spanka - One of the best experts on this subject based on the ideXlab platform.
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synthesis of n 4 2 2 amino 5 6 dihydro 4 3h oxo 7h pyrrolo 2 3 d pyrimidin 6 yl ethyl benzoyl l glutamic Acid a ring contracted analogue of 5 10 dideaza 5 6 7 8 Tetrahydrofolic Acid
Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
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Synthesis of N-{4-[2-(2-Amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- ethyl]benzoyl}-l-glutamic Acid: A Ring-Contracted Analogue of 5,10-Dideaza-5,6,7,8-Tetrahydrofolic Acid†
The Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
Edward C. Taylor - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Bridgehead Reactions of 9-Substituted 5,6,7,8,9,10-Hexahydro-5,9-Methanopyrimido[4,5-b]azocin-4(3H)-ones
HETEROCYCLES, 2003Co-Authors: Edward C. Taylor, Beena BhatiaAbstract:The condensation of a variety of 6-amino-4(3H)-pyrimidinones with 2-cyclohexen-1-one in water, and replacement of the bridgehead 9-hydroxy group in the resulting Michael/cyclization adducts with carbon nucleophiles, are described. These reactions have been exploited for the preparation of a novel bridged tricyclic analog of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF).
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synthesis of n 4 2 2 amino 5 6 dihydro 4 3h oxo 7h pyrrolo 2 3 d pyrimidin 6 yl ethyl benzoyl l glutamic Acid a ring contracted analogue of 5 10 dideaza 5 6 7 8 Tetrahydrofolic Acid
Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
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Synthesis of N-{4-[2-(2-Amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- ethyl]benzoyl}-l-glutamic Acid: A Ring-Contracted Analogue of 5,10-Dideaza-5,6,7,8-Tetrahydrofolic Acid†
The Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
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Novel 5-desmethylene analogs of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid as potential anticancer agents
The Journal of Organic Chemistry, 1992Co-Authors: Edward C. Taylor, Paul Gillespie, Mona PatelAbstract:The synthesis and biological activity of novel 5-desmethylene analogues of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, a potent antitumor agent presently indergoing clinical trails, are desscribed; These compounds are representative of a new series of optically pure analogues of DDATHF
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An intramolecular 1,3-dipolar cylcloaddition approach to 5,6,7,8-tetrahydro-4-ethoxy-6-hydroxymethyl-2-pivaloylamino-5-deazapteridin-5-(8H)-one, a potentially useful intermediate to 5-deaza-and 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid analogs
HETEROCYCLES, 1991Co-Authors: Edward C. Taylor, Partha S. RayAbstract:2-Amino-4,6-dichloro-5-formylpyrimidine was converted to the title compound (12), a potentially useful intermediate for the synthesis of 5-deaza- and 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid analogs. The key steps in the sequence were an intramolecular 1,3-dipolar cycloaddition of an in situ generated nitrile oxide (10b) to give the isoxazolo[3',4':4,5]pyrido[2,3-d]pyrimidine (11b) followed by reductive cleavage of the isoxazoline N-O bond
And Wendy B. Young - One of the best experts on this subject based on the ideXlab platform.
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synthesis of n 4 2 2 amino 5 6 dihydro 4 3h oxo 7h pyrrolo 2 3 d pyrimidin 6 yl ethyl benzoyl l glutamic Acid a ring contracted analogue of 5 10 dideaza 5 6 7 8 Tetrahydrofolic Acid
Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
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Synthesis of N-{4-[2-(2-Amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- ethyl]benzoyl}-l-glutamic Acid: A Ring-Contracted Analogue of 5,10-Dideaza-5,6,7,8-Tetrahydrofolic Acid†
The Journal of Organic Chemistry, 1996Co-Authors: Edward C. Taylor, And Wendy B. Young, Carsten SpankaAbstract:This paper describes the synthesis of N-{4-[2-(2-amino-5,6-dihydro-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]benzoyl}-l-glutamic Acid (4), which can be viewed as a ring-contracted analogue of 5,10-dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF, 1) in which the C-7 methylene group of the latter has been excised and C-6 joined to N-8. This compound exhibits significant activity as an inhibitor of the growth of human (CCRF-CEM) lymphoblastic leukemic cells in vitro and apparently acts by blocking de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GAR FTase).
Yoshifumi Maki - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of a novel 5-deaza-5-thia analogue of Tetrahydrofolic Acid, N-(p-{[(2-amino-6,7-dihydro-4-oxo-3H,8H-pyrimido[5,4-b][1,4]thiazin-6-yl)methyl]amino}benzoyl)glutamic Acid
Journal of The Chemical Society-perkin Transactions 1, 1994Co-Authors: Reiko Totani, Magoichi Sako, Kosaku Hirota, Yoshifumi MakiAbstract:N-(p-{[(2-Amino-6,7-dihydro-4-oxo-3H,8H-pyrimido[5,4-b][1,4]thiazin-6-yl)methyl]amino}benzoyl)glutamic Acid 4, a deaza-this analogue of Tetrahydrofolic Acid, was first synthesised as a diastereoisomeric mixture by the thermal condensation of 5-bromo-6-chloroisocytosine 6 with diethyl N-{p-[(3-amino-2-mercaptopropyl)amino]benzoyl}glutamate 5bvia the aliphatic S–N-type Smiles rearrangement in ethanolic pH 7 phosphate buffer solution followed by smooth alkaline hydrolysis of the ester protecting group.
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synthesis of a novel 5 deaza 5 thia analogue of Tetrahydrofolic Acid n p 2 amino 6 7 dihydro 4 oxo 3h 8h pyrimido 5 4 b 1 4 thiazin 6 yl methyl amino benzoyl glutamic Acid
Journal of The Chemical Society-perkin Transactions 1, 1994Co-Authors: Reiko Totani, Magoichi Sako, Kosaku Hirota, Yoshifumi MakiAbstract:N-(p-{[(2-Amino-6,7-dihydro-4-oxo-3H,8H-pyrimido[5,4-b][1,4]thiazin-6-yl)methyl]amino}benzoyl)glutamic Acid 4, a deaza-this analogue of Tetrahydrofolic Acid, was first synthesised as a diastereoisomeric mixture by the thermal condensation of 5-bromo-6-chloroisocytosine 6 with diethyl N-{p-[(3-amino-2-mercaptopropyl)amino]benzoyl}glutamate 5bvia the aliphatic S–N-type Smiles rearrangement in ethanolic pH 7 phosphate buffer solution followed by smooth alkaline hydrolysis of the ester protecting group.
Wolfgang Kern - One of the best experts on this subject based on the ideXlab platform.
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Impact of the simultaneous administration of the (+)- and (-)-forms of formyl-Tetrahydrofolic Acid on plasma and intracellular pharmacokinetics of (-)-Tetrahydrofolic Acid.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Eberhard Schleyer, Karl Lenhard Rudolph, Jan Braess, Michael Unterhalt, Gerhard Ehninger, Wolfgang Hiddemann, Wolfgang KernAbstract:Purpose: To detect possible interactions between (−)-formyl-Tetrahydrofolic Acid (leucovorin, (−)-fTHF) and (+)-formyl-Tetrahydrofolic Acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration. Methods: Plasma levels of (−)-fTHF, (−)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (−)-fTHF and (±)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of 14C-(−)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure. Results: The pharmacokinetic parameters obtained for (−)-fTHF following the administration of (−)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 μg · h/ml; maximum concentration, 12 μg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (±)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (−)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of 14C-(−)-mTHF did not depend on the presence of (+)-mTHF at either concentration. Conclusions: These data suggest that (−)-fTHF is not therapeutically superior to (±)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.
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impact of the simultaneous administration of the and forms of formyl Tetrahydrofolic Acid on plasma and intracellular pharmacokinetics of Tetrahydrofolic Acid
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Eberhard Schleyer, Karl Lenhard Rudolph, Jan Braess, Michael Unterhalt, Gerhard Ehninger, Wolfgang Hiddemann, Wolfgang KernAbstract:Purpose: To detect possible interactions between (−)-formyl-Tetrahydrofolic Acid (leucovorin, (−)-fTHF) and (+)-formyl-Tetrahydrofolic Acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration. Methods: Plasma levels of (−)-fTHF, (−)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (−)-fTHF and (±)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of 14C-(−)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure. Results: The pharmacokinetic parameters obtained for (−)-fTHF following the administration of (−)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 μg · h/ml; maximum concentration, 12 μg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (±)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (−)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of 14C-(−)-mTHF did not depend on the presence of (+)-mTHF at either concentration. Conclusions: These data suggest that (−)-fTHF is not therapeutically superior to (±)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.