Synthesis, radiolabeling with fluorine-18 and preliminary in vivo evaluation of a heparan sulphate mimetic as potent angiogenesis and heparanase inhibitor for cancer applications.

Heparan Sulfate (HS) mimetics are able to block crucial interactions of the components of the extracellular matrix in angiogenic processes and as such, represent a valuable class of original candidates for cancer therapy. Here we first report the synthesis and in vitro angiogenic inhibition properties of a conjugated, novel and rationally-designed octasaccharide-based HS mimetic. We also herein report its labeling with fluorine-18 and present the preliminary in vivo Positron Emission Tomography imaging data in rats. This constitutes one of the rare examples of labeling and in vivo evaluation of a synthetic, polysaccharide-based, macromolecule.

New series of N-substituted phenyl ketone oxime ethers: synthesis and bovine beta3-adrenergic agonistic activities.

A series of ten novel phenyl ketone oxime ethers substituted on the terminal nitrogen by either 1,3 benzodioxole, alkyl, aralkyl or aryl moiety were synthesized and tested for their activity at bovine beta3-adrenoceptors. The best compound, which was the benzodioxole dicarboxylate derivative, showed potent beta3-adrenergic agonistic activities in Chinese hamster ovary cells expressing the bovine beta3-adrenoceptors with Kact and Ki values better than compound CL 316,243 used as reference (14 +/- 6 nM and 203 +/- 71 nM, respectively). In this series three compounds showed an antagonistic activity. Structure-activity relationships in these ketone oxime ethers are discussed.

Synthesis and bovine beta 3-adrenergic agonistic activities of a novel series of aryloxypropanolamines.

We synthesized a novel series of 21 aryloxypropanolamine compounds characterized by N-alkyl, aralkyl, and aryl substituents. The compounds showed potent beta 3-adrenergic agonistic activities in Chinese hamster ovary cells expressing the bovine beta 3-adrenoceptors with Kact and Ki values of 4.2 +/- 3.0 nM and 459 +/- 169 nM respectively, for the ligand with the best compromise between potency and affinity. Structure-activity relationships are discussed.

Syntheses, activity and modeling studies of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists.

A series of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists was prepared. Affinity for the NMDA receptor was determined by binding assays using the specific radioligand [3H] (2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS-19755). The 3-alkylsulfonyl moiety was introduced by selective reduction of a carboxylic acid function followed by bromination, substitution by Na2SO3 and catalytic reduction. For the 4-alkylsulfonic derivatives the crucial step was the introduction of the 2-cyano function and its further conversion to 2-carboxylic acid. The most potent compound of the series was the pyridine (11a) [4-(sulfomethyl)pyridine-2-carboxylic acid] with a modest IC50 of 40 microM. A molecular modeling study has been undertaken to understand the pharmacological results. In a first step, a comparative modeling study of the active pyridine and the poorly active piperidine sulfonic acid derivatives 11a and 10a [4-(sulfomethyl)piperidine-2-carboxylic acid] and of the phosphonic homologues was performed. We propose that the binding geometry of the sulfonic moiety within the NMDA receptor is different from that of the phosphonic containing antagonists. In order to test this assumption, we have made, in a second step, a complete conformational analysis of the sulfonic acid derivatives, as well as some analogs taken from the literature, either active or inactive as NMDA antagonists. A preferred conformation of the sulfonic acids is proposed.