RESUMO
The title compound, C14H11Cl3N4O2, consists of two planar fragments which are nearly perpendicular to one another. The crystal packing is controlled by intra- and intermolecular C-H...O hydrogen bonds, and Cl...phenyl-ring-centroid and weak stacking interactions.
Assuntos
Compostos de Benzil/química , Purinas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura MolecularRESUMO
Doxorubicin-cephalosporin prodrug adapted to the development of elastases for the liberation of parent drug was synthesized on the basis of cephalosporanate sulfone esters.
Assuntos
Cefalosporinas/síntese química , Doxorrubicina/farmacologia , Ésteres/síntese química , Sulfonas/síntese química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cefalosporinas/farmacologia , Doxorrubicina/síntese química , Desenho de Fármacos , Ésteres/farmacologia , Humanos , Camundongos , Estrutura Molecular , Elastase Pancreática/antagonistas & inibidores , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Sulfonas/farmacologiaRESUMO
6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.
Assuntos
Antibióticos Antineoplásicos/síntese química , Azetidinas/síntese química , Penicilinas/síntese química , Animais , Antibióticos Antineoplásicos/farmacologia , Azetidinas/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Humanos , Camundongos , Penicilinas/farmacologiaRESUMO
The majority of nonantibacterial activities discovered for beta-lactam derivatives during the last 15 years are based on their ability to form a stable covalent complex with nucleophile in the active site of enzymes regulating fundamental physiological processes in mammalian organism such as serine and cysteine proteases, LDL phospholipase A(2), A-independent transacylase and some still indeciphered enzymes. Regulation of their catalytic activity both in vitro and in vivo by compounds designed on the cephalosporin, penicillin and 2-azetidinone base was successfully exploited in the treatment of inflammatory, respiratory, cardiovascular disorders, cancer and other pathologic processes. Availability of X-ray crystallographic data for target enzymes and computational molecular modelling in combination with wide possibilities of structural modifications for commercial natural and synthetic beta-lactams and the chiral blocks allow to consider this class of organic compounds as a perspective source of mechanism based nonantibacterial drugs.
Assuntos
Desenho de Fármacos , beta-Lactamas/química , Aciltransferases/antagonistas & inibidores , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/farmacologia , Cristalografia por Raios X , Interações Medicamentosas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Elastase Pancreática/antagonistas & inibidores , Fosfolipases A/antagonistas & inibidores , Antígeno Prostático Específico/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Trombina/antagonistas & inibidores , beta-Lactamas/farmacologiaRESUMO
Organoammonium hydroselenites were synthesized and investigated as potential selective, anticancer prodrugs. These compounds were studied in vitro on human fibrosarcoma (HT-1080), hamster kidney endothelial (BHK 21) and normal mouse embryonic fibroblasts (NIH 3T3). Most of them were very active against HT-1080 (0.6-5.3 g/ml). Amino acid hydroselenites readily increased the nitric oxide (NO) concentration in the culture medium of HT-1080 cells (up to TG(100)=1500%); however, 4-amidohydroximinomethylpyridinium hydroselenite (TG(100)=24%) and o-phenanthrolinium hydroselenite (TG(100)=50%) were free radical inhibitors. All compounds were glutathione peroxidase inhibitors; some of them could also prevent hydrogen peroxide degradation by inhibition of catalase. The influence of the investigated ammonium hydroselenites on tumor cell (HT-1080) morphology was examined. The substances studied were also active in vivo against sarcoma S-180. The role of organoammonium hydroselenites as free radical regulators and their therapeutic antitumor are discussed.
Assuntos
Antineoplásicos/farmacologia , Compostos Organosselênicos/farmacologia , Compostos de Amônio Quaternário/farmacologia , Animais , Antineoplásicos/síntese química , Catalase/antagonistas & inibidores , Catalase/metabolismo , Linhagem Celular Tumoral , Cricetinae , Ensaios de Seleção de Medicamentos Antitumorais , Endotélio/efeitos dos fármacos , Endotélio/fisiologia , Radicais Livres/metabolismo , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Peroxidase/metabolismo , Camundongos , Compostos Organosselênicos/síntese química , Compostos de Amônio Quaternário/síntese química , Sarcoma 180/tratamento farmacológico , Células Tumorais CultivadasRESUMO
Silicon and germanium containing pyridine aldoxime, ketoxime and amidoxime O-ethers have been prepared using phase transfer catalytic systems oxime alkyl halide solid KOH 18-crown-6 benzene and oxime alkyl halide solid K(2)CO(3) or Cs(2)CO(3) 18-crown-6 toluene. Cytotoxic activity of silicon and germanium containing pyridine oxime O-ethers was tested in vitro on two monolayer tumor cell lines: MG- 22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). O-[3-Yriethylsilylpropyl]- and O-[3-(1-methyl- 1-silacyclopentyl)propyl] oximes of pyridine aldehydes and ketones exhibit high cytotoxicity. Presence of methyl group in the pyridine ring considerably decreased activity of amidoxime O-ethers. Oxime ethers containing two elements are essentially inactive. For 2-acetylpyridine oxime ethers the activity increases in order of alkyl substituents: Et(3)GeCH(2)CH(2)SiMe(2)CH(2) < Et(3)SiCH(2)CH(2)CH(2) < (CH(2))(4)SiCH(2)CH(2)CH(2). Cytotoxicity of ketoxime O-ethers is considerably lower in comparison with aldoxime O-ethers.
RESUMO
Silicon containing pyridine and quinoline sulfides have been prepared using phase transfer catalytic system thiol/alkyl halide / solid KOH/18-crown-6 / toluene. The target S-ethers were isolated in yields up to 81%. The cytotoxicity of the synthesized compounds was studied. Among pyridine sulfides S-[3-(1-methyl- 1-silacyclohexyl)propyl] derivatives 5e and 6e exhibit the highest cytotoxicity. Aliphatic silicon derivatives were considerably less active. 8-[(Trimethylsilylmethyl)thio]quinoline (8a) exhibits the highest activity among quinoline sulfides.
RESUMO
Silacyclic derivatives of heteroaromatic sulfides have been prepared by using phase transfer catalytic (PTC) system thiol / silacyclopropyl iodide / solid K(2)CO(3) / 18-crown-6 / toluene. The target sulfides were isolated in yields up to 70 %. The S-derivatives of N-methylimidazolyl, benzoxazolyl and 1,3,4-triazolyl thiols selectively lowered the low density lipoprotein (LDL) level in mice with the high cholesterol diet in nutrition.