RESUMEN
Direct oxidation of 5-fluoro-1-(4-O-acetyl-3-deoxy-3-fluoro-6-O-trityl-beta-D-glucopyranosyl) uracil 9 led to the title compound 10 after a beta-elimination reaction. The formation of the hydrate of ketone 10 due to the highly electronegative fluorine atom in the a position to the carbonyl group, prompted us to carry out a comparative study of different methods of oxidation and to define the best strategy for the synthesis of such molecules. Results of in vitro and in vivo biological evaluations are reported.
Asunto(s)
Fluorouracilo/síntesis química , Fluorouracilo/farmacología , Monosacáridos/síntesis química , Monosacáridos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Nucleósidos/síntesis química , Nucleósidos/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
[see structure]. We report the synthesis of new cationic lipids. These amphiphiles present a hydrophobic domain connected to a guanidinium entity by an unsaturated glycoside scaffold. The synthetic strategy using amide or acetal linkage led to various mono- and bicatenar derivatives. Investigation of their physicochemical properties indicated that these new compounds compact DNA.
Asunto(s)
Glicósidos/química , Lípidos/síntesis química , Cationes , ADN/química , Conformación MolecularRESUMEN
A glycosylated analogue of dialkylamidoglycylcarboxyspermine was synthesized. The physico-chemical and transfecting properties of 11 were evaluated indicating that this cationic lipid forms stable particles at low charge ratio and is efficient for gene delivery.
Asunto(s)
Vectores Genéticos/metabolismo , Metabolismo de los Lípidos , Poliaminas/metabolismo , Transfección/métodos , Glicina/análogos & derivados , Glicina/síntesis química , Glicina/metabolismo , Glicosilación , Células HeLa , Humanos , Lípidos/síntesis química , Micelas , Poliaminas/síntesis química , Polielectrolitos , Espermina/análogos & derivados , Espermina/síntesis química , Espermina/metabolismo , Relación Estructura-ActividadRESUMEN
A safe and efficient synthesis of glycosylated polyethylenimine using titanium (IV) isopropoxide and sodium borohydride has been carried out as a substitute for the highly toxic sodium cyanoborohydride method currently used. Poryplexes formed between DNA and the various glycosylated polyethylenimines appeared to be much less cytotoxic than polyethylenimine (PEI)/DNA polyplexes.
Asunto(s)
Polietileneimina/síntesis química , Polietileneimina/farmacología , Transfección , Supervivencia Celular/efectos de los fármacos , Glicosilación , Polietileneimina/toxicidad , Células Tumorales CultivadasRESUMEN
In the context of our high-throughput organic synthesis program, we have studied the reactivity of special beta-keto esters toward the Biginelli reaction. We have found that a cyclic beta-keto ester reacts with one molecule of urea and two molecules of aldehyde to give a new family of spiro heterobicyclic aliphatic rings in good yields. Interestingly, the Biginelli product was not detected. After analysis of products using HPLC, 1H NMR, and 13C NMR, we have found that the reaction is driven by a regio-specific condensation of two molecules of aldehyde with the other reagents to afford only products harboring substituents exclusively in cis configuration. Monte Carlo minimization studies using MM2 force field suggest that cis products are energetically more stable than the trans counterparts. Together with previously reported data, these results suggest that the trans products were not obtained as result of steric hindrance produced by the equatorial position of one of the ring substituents. This new reaction is useful for high-throughput organic synthesis. Indeed, the new scaffold can be used to introduce additional groups in the molecules through remaining functional groups by a "domino strategy".
RESUMEN
Various analogs of statine, a remarkable amino acid component of the protease inhibitor pepstatine, were synthesized and evaluated as tripeptide derivatives for their activity against cathepsin D and HIV-1 protease.
Asunto(s)
Aminoácidos/farmacología , Catepsina D/antagonistas & inhibidores , Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacología , Aminoácidos/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Oligopéptidos/química , Pepstatinas/química , Inhibidores de Proteasas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Cationic lipids are widely used for in vitro gene transfer due to their efficiency. The major challenges for the improvement of in vivo cationic lipid-mediated gene delivery reside in the design of more biocompatible lipoplexes mimicking viral-mediated gene delivery and in understanding the fate of the lipoplexes within the cells.
Asunto(s)
Técnicas de Transferencia de Gen , Lípidos/química , Plásmidos/genética , Animales , Biotecnología , Cationes , Fenómenos Químicos , Química Física , Diseño de Fármacos , Vectores Genéticos , HumanosRESUMEN
We compared the biological activity of a new group of keto-C-glycosides to that of a narrow spectrum of unsaturated ketonucleosides in a panel of non-small-cell lung cancer (NSCLC) cells with various levels of intrinsic resistance to standard chemotherapy drugs. Unlike cisplatin, etoposide, adriamycin, or taxol, for which a significant difference in the cytotoxic effect was observed between sensitive cell lines (H460, H125, and MGH4) and drug-resistant cell lines (H661, MGH7, and FADU), nucleoside analogs were equally cytotoxic in NSCLC cell lines, with compound 92 being 10-fold more active than compound 43, 44, 81, or 161, while compound 3 was the least active. Apoptotic measurements with flow cytometric analysis of terminal uridine deoxynucleotide nick end-labeled cells revealed that the cytotoxic activity of these nucleosides correlated with their potency to induce apoptosis. Compound 92 triggered death in cells with wild-type p53, mutated p53, or p53 gene deletion. Our findings suggest that keto-C-glycosides may be promising alternative anticancer agents which merit further studies in in vivo cancer models refractory to standard chemotherapy drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Glicósidos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Nucleósidos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , División Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Genes p53/efectos de los fármacos , Genes p53/genética , Humanos , Neoplasias Pulmonares/patología , Células Tumorales CultivadasRESUMEN
The design, synthesis, cytotoxicity, and biological evaluation of carbohydrate/C-glycoside conjugates are described. The design concept is predicted on the idea that physiological barriers like the blood brain barrier could be crossed selectively by using glucose or glucose derivative/drug conjugates. The study demonstrates that, (1) carbohydrates and C-glycosides can be bonded at nonanomeric positions by the reaction of carbohydrate triflates with C-glycoside alkoxydes in the presence of DMPU; (2) there is a structure-activity relationship between the cytotoxicity of the conjugate and the nature of the carbohydrate residue; and (3) peracetylated hexose keto-C-glycoside conjugates are the most cytotoxic keto-C-glycosides.
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Glicósidos/química , Glicósidos/farmacología , Hexosas/química , Proteínas de Transporte de Monosacáridos/metabolismo , Pironas/química , Pironas/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1 , Glucósidos/síntesis química , Glicósidos/síntesis química , Hexosas/farmacología , Humanos , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Proteínas de Transporte de Monosacáridos/efectos de los fármacos , Pironas/síntesis química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
In a previous work, we have shown that some members of the family of keto-C-glycosides (KCGs) possess interesting biological properties as they exhibited cytotoxic effects at the nanomolar level on malignant cells. In this report, we selected six KCGs in order to investigate their selective cytotoxicity on several malignant epithelial and lymphoblastoid cells, as well as on their normal counterparts. For this purpose, we compared the activities of KCGs upon hepatoma cells and hepatocytes and upon lymphoma cells, normal lymphocytes and bone marrow cells. The tested drugs showed real discriminating cytotoxic effects since the cytotoxicity was several log greater on malignant than on non malignant cells. An in vitro comparative study of KCGs and some conventional chemotherapeutic agents showed that two of them were more potent than 5-fluorouracil, cis-platinum and etoposide. It is interesting to note that KCGs showed very low cytotoxic effects on either murine splenocytes, human peripheral blood lymphocytes or human bone marrow cells, indicating a weak immunosuppressive activity. The results presented here strongly suggest the selective cytotoxic activity of KCGs toward tumoral cells.
Asunto(s)
Antineoplásicos/farmacología , Glicósidos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Pironas/farmacología , Animales , Antineoplásicos/toxicidad , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Células de la Médula Ósea , Cisplatino/farmacología , Cisplatino/toxicidad , Doxorrubicina/farmacología , Doxorrubicina/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Etopósido/toxicidad , Fluorouracilo/farmacología , Fluorouracilo/toxicidad , Glicósidos/toxicidad , Humanos , Terapia de Inmunosupresión , Hígado/citología , Hígado/efectos de los fármacos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Pironas/toxicidad , Ratas , Ratas Endogámicas F344RESUMEN
We have examined the biological activity of keto-C-glycosides (KCGs), a new family of drugs displaying antiproliferative and cytotoxic properties on tumor cells. KCG1, the most powerful drug tested on epithelial derived neoplastic cells, was 25-125 times more cytostatic on epithelial cells than on lymphoma. By contrast, KCG10 proved to be more cytostatic on lymphoma than on epithelial cells. Correlations were found between the cytostaticity of KCGs and their lipophilicity, and are discussed within the framework of the structure-activity and the structure-selectivity relationships.