Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides.

The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Variable strategy toward carbasugars and relatives. 2. Diversity-based synthesis of beta-D-xylo, beta-D-ribo, beta-L-arabino, and beta-L-lyxo 4a-carbafuranoses and (4a-carbafuranosyl)thiols.

The silyloxy diene-based construction of carbasugars, previously exploited for the synthesis of four carbocyclic furanose and pyranose analogues, has been investigated further. By introducing a novel silylative cycloaldolization protocol and by adjusting a couple of minor transformations, the efficiency of this synthetic sequence was greatly improved. Through a series of lactone/thiolactone aldehyde cyclization precursors, four carbafuranoses (4a-carba-beta-D-xylofuranose, 4a-carba-beta-D-ribofuranose, 4a-carba-beta-L-arabinofuranose, and 4a-carba-beta-L-lyxofuranose) and four (carbafuranosyl)thiols [(4a-carba-beta-D-xylofuranosyl)thiol, (4a-carba-beta-D-ribofuranosyl)thiol, (4a-carba-beta-L-arabinofuranosyl)thiol, and (4a-carba-beta-L-lyxofuranosyl)thiol] were assembled. From this study, it was shown that these constructions tolerate a variety of precursors, and in many instances, they are suitable for scaling-up.

Variable strategy toward carbasugars and relatives. 1. Stereocontrolled synthesis of pseudo-beta-D-gulopyranose, pseudo-beta-D-xylofuranose, (pseudo-beta-D-gulopyranosyl)amine, and (pseudo-beta-D-xylofuranosyl)amine.

Four novel, chiral nonracemic carbasugars have been synthesized from 1,2-O-isopropylidene-D-glyceraldehyde. Furan- and pyrrole-based 2-silyloxy dienes--mimics of the alpha,gamma-dianions of gamma-hydroxy- and gamma-aminobutanoic acid, respectively--nicely served to complete the syntheses of two all-oxygen compounds, pseudo-beta-D-gulopyranose and pseudo-beta-D-xylofuranose, and two "anomeric" amino derivatives, (pseudo-beta-D-gulopyranosyl)amine (1,2,4-tri-epi-validamine) and (pseudo-beta-D-xylofuranosyl)amine. Two sequential, highly diastereoselective carbon-carbon bond-forming maneuvers, i.e., a vinylogous crossed aldol addition and an intramolecular aldolization, proved central to these constructions. The fact that readily available heterocyclic diene scaffolds can be employed in the assembly of a varied repertoire of carbasugars and analogues widens the prospects of dienoxy silane chemistry.

Antidermatophytic action of new 1-naphthylmethyl and benzo[b]thiophen-7-ylmethyl hydrazones related to inhibitors of squalene epoxidase.

Two series of hydrazonic compounds related to main classes of inhibitors of fungal squalene epoxidase (SE) were designed and prepared on the hypothesis of a pharmacophoric model. The antifungal activity of the new compounds was evaluated in vitro against dermatophytes, moulds and yeasts. Antidermatophytic activity resulted for several hydrazones, particularly for those containing a tett-butylacetylenic group, supporting the hypothesis that the introduction of a hydrazonic function in the model could retain the antimycotic activity.

The utility of furan-, pyrrole-, and thiophene-based 2-silyloxy dienes as demonstrated by modular synthesis of annonaceous acetogenin core units and their pyrrolidine and thiolane analogues.

We report a modular strategy for obtaining the core units of annonaceous acetogenins and their nitrogen and sulfur analogues, which generates great structural diversity. This synthesis is based on the application of a reiterative vinylogous addition protocol involving a unique triad of silyloxy diene modules, 2-[(tert-butyldimethylsilyl)oxy]furan (TBSOF), N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert-butyldimethylsilyl)oxy]thiophene (TBSOT) and suitable heteroatom-stabilized carbenium ions. By combining TBSOF, TBSOP, and TBSOT nucleophilic synthons with certain tetrahydrofuran, pyrrolidine, and thiolane acceptors, the construction of varied, adjacently linked oligo-heterocyclic motifs related to the core segments of the annonaceous acetogenins is assured. At first, the reliability of the pivotal coupling maneuver was certified, by assembling a collection of 18 model constructs, covering all oxygen, nitrogen, and sulfur heteroatom combinations (i.e., compounds 7-9, 13-15, and 19-21). This uniformed protocol was then suited to forge advanced bis-tetrahydrofuran, bis-pyrrolidine, and bis-thiolane scaffolds encompassing the heterocyclic core portion of various binuclear annonaceous acetogenins and relatives. The utility of this synthesis was demonstrated by the preparation of a repertoire of eight isomeric bis-tetrahydrofuran units, 41-48, two bis-pyrrolidine units, 62 and 63, and four bis-thiolane units, 78-81.

Anti-inflammatory and analgesic amides: new developments.

A series of substituted N-cycloalkyl benzamides, cinnamamides, and indole-3-carboxamides were synthesized and evaluated for their analgesic, antiinflammatory activities as well as for their gastrointestinal irritation liability. Indomethacin was used as reference drug in both tests. Compounds 1k, 1b, 1h, 1j, and 1g were the most active in the antiinflammatory paw edema inhibition test, with a sharply dose-dependent effect. In terms of the analgesic activity (acetic acid writhing test), the most active compound was 5a followed by 3a, but many other compounds were found to have a non-negligible potency. Even in this case, the effect was dose dependent.

Synthesis of N-[4-(propyl)cyclohexyl]-amides with anti-inflammatory and analgesic activities.

Seventeen (un)substituted N-[4-(propyl)cyclohexyl]-amides (6a-h, 7a-h and 8) were synthesized and tested as anti-inflammatory and analgesic agents. The substituents on the aromatic ring were chosen in order to study the influence of electron-withdrawing or electron-donating residues, that change the electronic density on the aromatic moiety. The pharmacological results allow drawing some preliminary considerations on structure-activity relationships.