RESUMO
Oxovanadium (IV) complexes of the cyclic polyols conduritol C (cond) and myo-inositol (inos) of stoichiometry Na(2)[VO(cond)(2)].2H(2)O and Na(2)[VO(inos)(2)].H(2)O were obtained in aqueous alkaline solutions. They were characterized by infrared and UV-Vis spectroscopies, thermoanalytical (thermogravimetric and differential thermal analysis) data and magnetic susceptibility measurements. The biological activities of the complexes on the proliferation, differentiation and glucose consumption were tested on osteoblast-like cells in culture. Conduritol C and myo-inositol did not produce any effect on these parameters. Normal and tumoral cell proliferation was inhibited about (ca.40-60%) by the two oxovanadium (IV) complexes in concentrations as low as 100microM. The complexes were also inhibitory on cell differentiation (ca. 70-80%) while they stimulate glucose consumption. Comparisons of these effects with those of the oxovanadium (IV) cation, under the same experimental conditions, were also performed.
Assuntos
Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Vanadatos/síntese química , Vanadatos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cicloexanóis/síntese química , Cicloexanóis/química , Cicloexanóis/farmacologia , Cicloexenos , Glucose , Inositol/síntese química , Inositol/química , Inositol/farmacologia , Camundongos , Estrutura Molecular , Compostos Organometálicos/química , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Ratos , Espectrofotometria , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Vanadatos/químicaRESUMO
epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoenzymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical debromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol, and deoxy derivatives of epi-inositol.
Assuntos
Bromobenzenos/química , Inositol/química , Oxigenases/química , Catálise , Clorofórmio , Compostos de Epóxi/química , Hidrólise , Inositol/síntese química , Modelos Químicos , Oxigênio/metabolismo , Estereoisomerismo , Especificidade por SubstratoRESUMO
The design of more effective therapies for metastatic disease involves development of new compounds able to specifically block the malignant process. We demonstrated previously that a new synthetic nitrogenated compound 3'-1-chloroethyl-2,3-dihydro-1H-imidazo-(2, 1-i)-purine-4-ium-7-yl-3'-deoxy-1',5', 6'-tri-O-(methylsulfonyl)-muco-inositol chloride (DIC) had an anti-proliferative activity on tumor cells in vitro. In the present work we demonstrate that DIC induces apoptosis on the LM3 murine mammary adenocarcinoma cell line in vitro and has anti-angiogenic activity in vivo. We also evaluated toxicity, biodistribution and anti-neoplastic properties of DIC in vivo. Toxicity studies allowed us to establish the LD50 (750 mg/kg body weight). Administration of 250 mg/kg/day (LD10) for 6 days did not cause overt toxic effects. Biodistribution assays revealed that DIC was rapidly eliminated (60% at t=10 min), although it accumulated in tumor tissue at higher concentrations than in other tissues. Daily s.c. treatment with DIC (LD10) for 24 days significantly reduced the number of spontaneous lung metastases. These results suggest that DIC has the ability of impairing the metastatic development by inhibiting angiogenesis and inducing apoptosis on tumor cells.