RESUMO
The activity of three pyrroles and four pyrrolizines is compared in several different experimental leukemias and solid tumors in mice. Two compounds were particularly noteworthy, the bis(N-cyclohexylcarbamate) and the bis[N-(2-propyl)] derivatives of 2,3-dihydro-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine. These two compounds showed a very high level of activity against B16 melanocarcinoma, CD8F1 mammary tumor, colon tumor 26, and colon tumor 38, and a significant number of "cures" were recorded. The isopropyl compound was more potent than the cyclohexyl compound, but both showed a similar profile of activity.
Assuntos
Neoplasias Experimentais/tratamento farmacológico , Pirróis/uso terapêutico , Pirrolidinas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Leucemia Experimental/tratamento farmacológico , Masculino , Camundongos , Relação Estrutura-AtividadeRESUMO
5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods. The best preparative procedure was the one starting from benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-2,3-O-isopropylidene-beta-D-ribof uranoside (15) that was obtained almost quantitatively by condensation of benzyl 2,3-O-isopropylidene-beta-D-ribofuranoside (8) with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate (2). After de-O-isopropylidenation of 15, the crystalline product, benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-beta-D-ribofuranoside (16), was de-O-benzylated catalytically to 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-glucopyranosyluronate)-D-ribofuranose (17). Compound 17 was acetylated to crystalline 5-O-(methyl 2',3',4'-tri-O-acteyl-beta-D-glucopyranosyluronate)-1,2,3-tri-O-acetyl-beta-D-ribofuranose (18) and condensed with trimethylsilylated 5-fluorouracil of 5-fluorocytosine in the presence of SnCl4 to afford the corresponding protected nucleosides 5 and 19 in good yields. Saponification of these compounds gave 5'-O-beta-D-glucuronides of 5-fluorouridine and 5-fluorocytidine (20 and 21) isolated as their crystalline N salts. These glucuronides were substrates of both bacterial and bovine beta-glucuronidase. They were, as expected, much less toxic against several leukemia cell lines in tissue culture.
Assuntos
Antineoplásicos/síntese química , Citidina/análogos & derivados , Uridina/análogos & derivados , Células Cultivadas , Citidina/síntese química , Citidina/farmacologia , Glucuronatos/síntese química , Neoplasias Experimentais/tratamento farmacológico , Uridina/síntese química , Uridina/farmacologiaRESUMO
2-Chloromethylbenzo[b]furans were prepared in high overall yield from the corresponding chloroethylphenyl ethers through chloroepoxide and alpha-chlorophenylacetone intermediates.
Assuntos
Benzofuranos/síntese química , MétodosRESUMO
The syntheses for the bis(N-methylcarbamates) 3, 4a, 4b, and 5 are described. All four compounds were active in the in vivo P388 lymphocytic leukemia assay, with 3 being the most active.
Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Animais , Carbamatos/farmacologia , Carbamatos/toxicidade , Feminino , Leucemia P388/tratamento farmacológico , Masculino , Camundongos , Relação Estrutura-AtividadeRESUMO
A series of phenyl-substituted derivatives of 1,2-dimethyl-3,4-bis(hydroxymethyl)-5-phenylpyrrole bis(N-methylcarbamate) (1) were synthesized and tested for antileukemic activity against P388 lymphocytic leukemia in the mouse. All of the compounds tested, 1a--r, showed significant activity in this assay. Selected derivatives of 1 were tested against several bacteria and were found to have little or no antibacterial activity in the systems examined.