Synthesis and binding mode of heterocyclic analogues of suramin inhibiting the human basic fibroblast growth factor.

The design, synthesis, and biological evaluation of a series of pyrrole and pyrazole congeners 2 of suramin, directed toward the development and identification of new ligands that complex the human fibroblast growth factor (bFGF), thereby inhibiting tumor-promoted angiogenesis, is reported. Compounds 2 were evaluated for their ability to inhibit binding of bFGF to its receptor, in vivo bFGF-induced angiogenesis, and neovascularization of the chorioallantoic membrane in comparison with suramin. These assays showed that ligands 2 exhibit moderate to good activity, comparable to that of suramin, and are less toxic than suramin itself. In this study, affinity data of ligands in combination with the crystal structure of bFGF were used to explain structure-affinity relationships and to gain an insight into the possible mode of ligand-protein interaction. Due to the lack of experimental structural data on the ligand-bFGF complexes, molecular mechanics techniques were used to obtain putative bioactive conformations and to generate docked complexes with the three-dimensional structure of bFGF. These experiments led to suggest that compounds 2 give rise to 1:1 complexes with bFGF through an unprecedented, bidentate attachment of their naphthylsulfonate groups to two main domains, commonly referred to as the heparin binding site and the receptor binding site, on bFGF, thus preventing the interaction of the growth factor with its receptor.

Efecto del sistema killer sobre especies del género candida aisladas de secreción vaginal / Effect of killer system over genus candida species isolated from vaginal secretion

En 348 análisis micológicos de secreción vaginal realizados en el CEREMIC de la Facultad de Ciencias Bioquímicas y Farmacéuticas de la UNR, se determinó un 15 porciento de resultados positivos para diferentes especies del género candida (53 muestras). El objetivo de este trabajo fue: clasificar las levaduras, su sensibilidad al sistema killer SKI, determinar el tipo killer más frecuente y su relación con la reacción inflamatoria. A su vez, estos resultados se cotejaron con los hallados en otros materiales clínicos. Entre las diversas especies de levaduras aisladas, los mayores porcentajes correspondieron a candida albicans (9,48 por ciento), candida tropicalis (1,72 por ciento), candida parapsilosis, candida glabrata (0, 86 por ciento), y en un 0,29 por ciento a otras especies de candida. El tipo killer más frecuente fue 111 (64 por ciento); siendo tambien el más encontrado en materia fecal (67 por ciento) y en piel y faneras (82 por ciento)

In vivo activity of novel sulphonic derivatives of distamycin A.

Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.

Biological profile of FCE 24517, a novel benzoyl mustard analogue of distamycin A.

FCE 24157 (chemically (beta-[1-methyl-4-(1-methyl-4--[1-methyl-4-(4-N,N- bis(2-chloroethyl) amino-benzene-1-carboxy-amido) pyrrole-2-carboxiamido]pyrrole-2-carboxyamido)pyrrole-2-c arboxyamido]) propionamidine, hydrochloride) is a distamycin A (Dista A) derivative bearing a benzoyl mustard moiety instead of the formyl group at the N-terminal. Contrary to Dista A, FCE 24517 has been found to display potent cytotoxic activity on human and murine tumour cell lines. The compound maintains activity on melphalan (L-PAM)-resistant cells, whereas cross-resistance is observed on doxorubicin-(DX)-resistant cells. In vivo, FCE 24517 was found to possess evident antineoplastic activity on a series of murine transplanted solid tumours and human tumour xenografts. The following neoplasms were in fact found to be sensitive to FCE 24517 treatment: M14 human melanoma xenograft, N592 human small cell lung carcinoma, MTV murine mammary carcinoma, Colon 38 murine carcinoma, PO2 murine pancreatic carcinoma and M5076 murine reticulosarcoma. Lower effectiveness was observed against the murine P388 and Gross leukaemia, Lewis lung murine carcinoma, LoVo human colon carcinoma xenografts and A459 human lung adenocarcinoma. Against the murine L1210 leukaemia, FCE 24517 displayed a clear activity only when the tumour was transplanted i.p. and treatment was given i.p., whereas only marginal activity was seen against this leukaemia if transplanted i.v. and the drug was given i.v. As true also in vitro, FCE 24517 was effective against i.p. implanted L1210 leukaemia resistant to L-PAM. The mode(s) of action of this new compound is under active investigation.

Cephalosporins. II. Synthesis and structure-activity relationships of new 7-vinylenethioacetamido and thioacrylamido cephalosporins.

The synthesis and in vitro structure-activity relationships of 7-vinylenethioacetamido and thioacrylamido cephalosporins with various substituents at the 3-position are described. 7(Z)-beta-Vinylenethioacetamido cephalosporins proved the most active against Gram-positive and Gram-negative bacteria. 7-[(Z)-beta-Cyanovinylenethioacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (K 13101, 40) was several times more active in vitro than cefazolin.

New broad-spectrum alkylthio cephalosporins.

A series of 7-substituted alkyl-thio-acylaminocephalosporins with the following general formula were prepared and tested for in vitro antibacterial activity: (formula: see text). We tried in our research to find any relationship between antibacterial activity and pharmacokinetic properties on the one hand, and chemical structure on the other. The most interesting products were also studied for their in vivo antibacterial activity in experimental acute systemic infections in the mouse.