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1.
J Org Chem ; 66(11): 3726-38, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-11374991

RESUMO

Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH(2)C(6)H(3)(OMe)(2)(-3',4'), which resulted in a known pentultimate precursor (9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors of cell division.


Assuntos
Antimetabólitos Antineoplásicos/síntese química , Antagonistas do Ácido Fólico/síntese química , Glutamatos/síntese química , Guanina/análogos & derivados , Guanina/síntese química , Antimetabólitos Antineoplásicos/química , Antagonistas do Ácido Fólico/química , Glutamatos/química , Guanina/química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Pemetrexede
2.
Br J Haematol ; 111(2): 482-90, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11122088

RESUMO

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Dor no Peito/imunologia , Citocinas/sangue , Derrame Pleural/imunologia , Traço Falciforme/imunologia , Doença Aguda , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Sistema do Grupo Sanguíneo Duffy , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Interleucina-8/análise , Interleucina-8/genética , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Traço Falciforme/sangue , Síndrome
3.
Invest New Drugs ; 14(3): 281-5, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8958183

RESUMO

A new and extremely efficient synthesis of DDATHF from 4-vinylbenzoic acid and bromomalondialdehyde as precursors has been developed which proceeds in 48% overall yield.


Assuntos
Antimetabólitos Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Antagonistas do Ácido Fólico/síntese química , Estirenos/química , Tetra-Hidrofolatos/síntese química , Malondialdeído/análogos & derivados , Malondialdeído/química , Estrutura Molecular
4.
Mol Pharmacol ; 48(2): 326-33, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7651366

RESUMO

The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.


Assuntos
Hidroximetil e Formil Transferases , Peptídeo Sintases/metabolismo , Tetra-Hidrofolatos/metabolismo , Aciltransferases/antagonistas & inibidores , Animais , Divisão Celular/efeitos dos fármacos , Cinética , Leucemia/patologia , Fígado/enzimologia , Camundongos , Fosforribosilglicinamido Formiltransferase , Especificidade por Substrato , Suínos , Tetra-Hidrofolatos/química , Tetra-Hidrofolatos/farmacologia , Células Tumorais Cultivadas
6.
J Med Chem ; 35(23): 4450-4, 1992 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-1447744

RESUMO

N-[4-[2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid (15), prepared in five steps from 2-pivaloyl-7-deazaguanine, has been found to be an antitumor agent with its primary site of action at thymidylate synthase rather than purine synthesis. This compound appears to be a promising candidate for clinical evaluation.


Assuntos
Antineoplásicos/síntese química , Glutamatos/síntese química , Guanina/análogos & derivados , Timidilato Sintase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Glutamatos/química , Glutamatos/uso terapêutico , Guanina/síntese química , Guanina/uso terapêutico , Humanos , Leucemia L1210/tratamento farmacológico , Leucemia Linfoide/tratamento farmacológico , Camundongos , Pemetrexede , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
J Med Chem ; 35(6): 1109-16, 1992 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-1552503

RESUMO

The synthesis and biological evaluation of a number of analogues of N-[4-[4-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidyl) butyl]benzoyl]-L-glutamic acid (2) (7-DM-DDATHF), an acyclic modification of the novel folate antimetabolite 5,10-dideazatetrahydrofolic acid (DDATHF), are described. The synthetic procedure utilized previously for the synthesis of 2, 15, and 16 was extended to the preparation of analogues modified in the benzoyl region with thiophene and methylene groups replacing the benzene ring (compounds 27a-c) and in the glutamate region with aspartic acid and phenylalanine replacing L-glutamic acid (compounds 36, 37). The 2-amino-4,6-dioxo derivative 33 was obtained from intermediate 30 via a palladium-catalyzed carbon-carbon coupling reaction with diethyl (4-iodobenzoyl)-L-glutamate, followed by reduction and removal of protecting groups with base. Cell culture cytotoxicity studies of all of the above acyclic analogues of DDATHF against CCRF-CEM human lymphoblastic leukemic cells gave IC50s ranging from 0.042 greater than 48 microM. Inhibition and cell culture reversal studies against isolated enzymes suggest the mode of action of these compounds. Compound 2 was only 3-fold less inhibitory toward glycinamide ribonucleotide formyltransferase (GARFT, isolated from L1210 leukemic cells) than DDATHF itself. These acyclic analogues were less efficient substrates for the enzyme folylpolyglutamate synthetase (FPGS) compared with their bicyclic counterparts. Moderate antitumor activity was observed for compound 2 against 6C3HED lymphosarcoma and C3H mammary adenocarcinoma in vivo.


Assuntos
Antineoplásicos/síntese química , Tetra-Hidrofolatos/síntese química , Tetra-Hidrofolatos/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular , Células Cultivadas , Humanos , Leucemia Linfoide/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C3H , Relação Estrutura-Atividade , Tetra-Hidrofolatos/química
8.
Biochemistry ; 30(7): 1997-2006, 1991 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-1993209

RESUMO

We have investigated the structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF) that determine the activity of this compound as an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT) purified from mouse L1210 cells. 5-Deazatetrahydrofolate was as good an inhibitor of GARFT as DDATHF, indicating that isosteric replacement of nitrogen by carbon at the 5-position of tetrahydrofolate is sufficient for inhibition of GARFT. 5,10-Dideazafolic acid, 5,8,10-trideazatetrahydrofolate, and 2-desamino-5,10-dideazatetrahydrofolate were poor inhibitors of GARFT, indicating that a reduced pyridopyrimidine ring, N-8, and the 2-amino group of DDATHF, respectively, play an important role in the binding of tetrahydrofolate analogues to this enzyme. DDATHF analogues in which the phenyl ring was replaced either by a cyclohexyl ring or by methylene groups retained activity as inhibitors. 5,10-Dideazatetrahydrohomofolate was about 6 times more potent as an inhibitor of GARFT than DDATHF, but 5,10-dideazatetrahydronorfolate had about one-fifth of the activity of DDATHF. An analogue of DDATHF in which the glutamic acid side chain was replaced by aspartic acid (which was not a substrate for polyglutamation and was only weakly cytotoxic) was equiactive with DDATHF as an inhibitor of purified GARFT. Surprisingly, 5,10-dideazatetrahydropteroic acid was about as active as DDATHF as an inhibitor of GARFT, an indication that the glutamic acid in the side chain of DDATHF does not play a role in this ligand-enzyme interaction. The polyglutamate derivatives of DDATHF bound up to 100 times tighter to GARFT than DDATHF itself; longer chain polyglutamates conformed to Goldstein's zone B behavior under experimental conditions and were projected to be in zone C, i.e., stoichiometric inhibition, in vivo. We conclude that the presence of carbon at the 5-position of tetrahydrofolate analogues is sufficient for inhibition of GARFT, that N-8 and the 2-amino group are involved in binding of DDATHF to GARFT, probably through hydrogen bonds, and that the structures of the phenyl ring and amino acid side chain of DDATHF analogues are not primary determinants of GARFT inhibition by monoglutamate forms of these compounds. We also conclude that polyglutamation plays a major role in the potent cytotoxicity of DDATHF.


Assuntos
Aciltransferases/antagonistas & inibidores , Antagonistas do Ácido Fólico/farmacologia , Hidroximetil e Formil Transferases , Tetra-Hidrofolatos/farmacologia , Aciltransferases/isolamento & purificação , Animais , Eletroforese em Gel de Poliacrilamida , Cinética , Leucemia L1210/enzimologia , Camundongos , Estrutura Molecular , Peso Molecular , Fosforribosilglicinamido Formiltransferase , Estereoisomerismo , Relação Estrutura-Atividade
9.
J Biol Chem ; 264(35): 21047-51, 1989 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-2592365

RESUMO

The diasteromers of 5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF) differing in chirality about carbon 6 were resolved and studied as inhibitors of folate-dependent processes in mouse leukemia cells. Both diastereomers of DDATHF were found to be potent inhibitors of leukemia cell growth due to effects on de novo purine synthesis. Cell growth inhibition by these compounds was prevented by 5-formyltetrahydrofolate in a dose-dependent manner. This indicated that the effects of the DDATHF diastereomers were due to inhibition of folate-dependent processes. Metabolite reversal experiments indicated that 5'-phosphoribosylglycinamide formyltransferase was the major site of action of these compounds in mouse cells. Another site in de novo purine synthesis was affected at higher concentrations of diastereomer B in L1210 cells. Low concentrations of both diastereomers were found to inhibit pure L1210 5'-phosphoribosylglycinamide formyltransferase competitively with the folate substrate. The two diastereomers were also efficient substrates for mouse liver folylpolyglutamate synthetase. We conclude that the 6R- and 6S-diastereomers of DDATHF are remarkably similar and equiactive antimetabolites inhibitory to de novo purine synthesis and that the biochemical processes involved in their cytotoxicity display little stereochemical specificity.


Assuntos
Aciltransferases/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Hidroximetil e Formil Transferases , Leucemia L1210/enzimologia , Peptídeo Sintases/metabolismo , Purinas/metabolismo , Tetra-Hidrofolatos/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Cinética , Fígado/enzimologia , Metotrexato/farmacologia , Camundongos , Fosforribosilglicinamido Formiltransferase , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/enzimologia
10.
J Med Chem ; 32(7): 1517-22, 1989 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2738886

RESUMO

Syntheses of 5-deaza-5,6,7,8-tetrahydrofolic acid (7a) and its 10-formyl (7b), 10-acetyl (7c), and 10-methyl (7d) derivatives are described. These compounds, prepared as analogues of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), the lead compound of a new class of folate antimetabolites, exhibit potent growth inhibition against leukemic cells in culture as well as substantial antitumor activity against transplantable murine solid tumors in vivo.


Assuntos
Antineoplásicos/síntese química , Tetra-Hidrofolatos/síntese química , Animais , Fenômenos Químicos , Química , Humanos , Leucemia L1210/patologia , Camundongos , Nitrogênio , Purinas/antagonistas & inibidores , Purinas/biossíntese , Tetra-Hidrofolatos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos
11.
J Biol Chem ; 264(1): 328-33, 1989 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-2909524

RESUMO

5,10-Dideazatetrahydrofolate (DDATHF) is a new antimetabolite designed as an inhibitor of folate metabolism at sites other than dihydrofolate reductase. DDATHF was found to inhibit the growth of L1210 and CCRF-CEM cells in culture at concentrations in the range of 10-30 nM. The inhibitory effect of DDATHF on the growth of L1210 and CCRF-CEM cells was reversed by either hypoxanthine or aminoimidazole carboxamide. Growth inhibition by DDATHF was prevented by addition of both thymidine and hypoxanthine, but not by thymidine alone. 5-Formyltetrahydrofolate reversed the effects of DDATHF in a dose-dependent manner. DDATHF had no appreciable inhibitory activity against either dihydrofolate reductase or thymidylate synthase in vitro, but was found to be an excellent substrate for folylpolyglutamate synthetase. DDATHF had little or no effect on incorporation of either deoxyuridine or thymidine into DNA, in distinct contrast to the effects of the classical dihydrofolate reductase inhibitor, methotrexate. DDATHF was found to deplete cellular ATP and GTP over the same concentrations as those inhibitory to leukemic cell growth, suggesting that the locus of DDATHF action was in the de novo purine biosynthesis pathway. The synthesis of formylglycinamide ribonucleotide in intact L1210 cells was inhibited by DDATHF with the same concentration dependence as inhibition of growth. This suggested that DDATHF inhibited glycinamide ribonucleotide transformylase, the first folate-dependent enzyme of de novo purine synthesis. DDATHF is a potent folate analog which suppresses purine synthesis through direct or indirect inhibition of glycinamide ribonucleotide transformylase.


Assuntos
Purinas/biossíntese , Tetra-Hidrofolatos/farmacologia , Células Tumorais Cultivadas/citologia , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Glicina/análogos & derivados , Glicina/biossíntese , Humanos , Cinética , Leucemia L1210/patologia , Fígado/enzimologia , Metotrexato/farmacologia , Camundongos , Purinas/antagonistas & inibidores , Ribonucleotídeos/biossíntese , Células Tumorais Cultivadas/efeitos dos fármacos , gama-Glutamil Hidrolase/metabolismo
12.
J Pharm Sci ; 77(12): 999-1002, 1988 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3149673

RESUMO

The electrochemical characteristics of the antitumor agents methotrexate and alpha-difluoromethylornithine were determined as their iminium derivatives. Iminium formation from methotrexate is accomplished in vivo via protonation by enzyme. The requisite imine precursor is generated from alpha-difluoromethylornithine by condensation with enzyme containing pyridoxal phosphate. Electroreduction occurs in the range of -0.2 to -0.6 V. The relationship of reduction to structure is discussed. A possible mode of anticancer action involving electron transfer is presented.


Assuntos
Eflornitina/análise , Metotrexato/análise , Fenômenos Químicos , Química , Eletroquímica , Concentração de Íons de Hidrogênio , Fosfato de Piridoxal/análise
15.
J Med Chem ; 20(9): 1215-8, 1977 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-411935

RESUMO

A number of homologous 2,4-diaminocycloalka[g]pteridines varying in ring size from 5 to 15 were prepared by (a) condensation of aminomalononitrile tosylate with alpha-oximinocycloalkanones, deoxygenation of the resulting 2-amino-3-cyanocycloalka[b]pyrazine 1-oxides, and guanidine cyclization; (b) guanidine cyclization of the above pyrazine 1-oxides to give 2,4-diaminocycloalka[g]pteridine 8-oxides, followed by deoxygenation; or (c) condensation of 2,4,5,6-tetraaminopyrimidine with a cycloalka-1,2-dione (for the cyclohepta- and cycloocta[g]pteridines only). These compounds were examined for their activity as dihydrofolate reductase inhibitors against Lactobacillus casei, rat liver, L1210, and Trypanosoma cruzi. Activity was found to depend upon ring size, with the greatest activity exhibited by the cyclododeca derivatives 31.


Assuntos
Antagonistas do Ácido Fólico , Pteridinas , Animais , Lacticaseibacillus casei/enzimologia , Leucemia L1210/enzimologia , Fígado/enzimologia , Pteridinas/síntese química , Pteridinas/farmacologia , Ratos , Relação Estrutura-Atividade
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