Maria Luisa Gelmi

A new synthetic procedure to spiro[cyclohexane-1,3'-indoline]-2', 4-diones

Abstract A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefskys diene 2 . Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7 . Using a ‘one pot reaction’, starting from 1 and 2 , compounds 7 were obtained in satisfactory overall yield.

5(4H)-Oxazolones. Part X. Acid and base effects on the translactonization reaction of 4-(2-Oxa-alkylidene)-5(4H)-oxazolones: New synthesis of 5-alkylidene-3-benzoylamino-2(5H)-furanones

Abstract 4-(2-Oxa-alkylidene)-5(4H)-oxazolones (azlactones) 1 can be transformed in acidic conditions (anhydrous HBr/CHCl3) into 5-alkylidene-3-benzoylamino-2(5H)-furanones 2 which have Z configuration at the exocyclic double bond. The same reaction conducted in acetic acid as solvent gives, besides the alkylidene-furanones 2, the furanyl acetates 5. The result of azlactone transformation in the presence of base (DBU) depends on the steric hindrances in the starting material. The less hindered oxazolones 1a, b give condensation products 8, whereas the more hindered azlactobe 1c gives furanone 2c or, in presence of an alkylating agent, furanone 2d.

1H‐Azepine‐4‐amino‐4‐carboxylic Acid: A New α,α‐Disubstituted Ornithine Analogue Capable of Inducing Helix Conformations in Short Ala‐Aib Pentapeptides

A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.

Chemistry of Biologically Active Isothiazoles

The isothiazole ring as well as the corresponding benzo- and heterocondensed rings are present in many chemically interesting compounds. The isothiazole ring can be a substituent of a bioactive scaffold or the pharmacophore of bioactive molecules. New compounds have been designed, synthesised and tested towards different biological targets and, in many cases, they display interesting pharmaceutical activities. Different SAR studies are reported starting from already known isothiazole derivatives or from new compounds characterised by a particular substitution pattern aiming to improve the biological activity. Agrochemical applications are also reported.

A new synthesis of staurosporinone

Abstract A new six steps synthesis of staurosporinone 4, starting from 3-cyano-3-(1H-indol-3-yl)-2-oxo-propionic acid ethyl ester 5, is reported.

Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase.

A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC(50) of 2 microM and blocked the growth of the bloodstream parasite in vitro with an ED(50) of 10 microM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.

Chemotactic effect of prorenin on human aortic smooth muscle cells: a novel function of the (pro)renin receptor

AIMS The discovery of a specific prorenin receptor (PRR) suggests a biological function of prorenin that is independent of angiotensin I production. In the present study, we investigated the role of PRR on smooth muscle cell (SMC) migration. METHODS AND RESULTS PRR was expressed in human mammary arteries and in cultured human aortic SMCs. Prorenin induced SMC migration in a dose-dependent manner, as assessed by Boyden chamber chemotaxis assay, and increased SMC random motility, as determined by video microscopy. The prorenin decoy peptide inhibited SMC migration in response to prorenin, and knockdown of PRR by small interfering RNA completely inhibited the migratory response to prorenin, demonstrating that the chemotactic action of prorenin is mediated by the PRR. Prorenin induced cytoskeleton reorganization and lamellipodia formation and increased the intracellular levels of both RhoA-GTP and Rac1-GTP through PRR. These effects were required for SMC migration, because the suppression by small interfering RNA of either Rac1 or RhoA GTP-bound forms completely blocked the PRR-mediated chemotactic effect. Prorenin also induced the formation of larger focal adhesions and cleavage of the focal adhesion kinase (pp125(FAK)) into two main fragments with molecular weights of 50 and 90 kDa. The generation of these two fragments of pp125(FAK) was reduced by the calpain inhibitor ALLN, which also inhibited SMC migration in response to prorenin. CONCLUSIONS These results demonstrate that prorenin is a chemotactic factor for human aortic SMCs expressing PRR. This effect is elicited through reorganization of the cytoskeleton and focal adhesion, activation of RhoA and Rac1, and calpain-mediated cleavage of pp125(FAK).

A highly diastereoselective synthesis of α-hydroxy-β-amino acid derivatives via a Lewis acid catalyzed three-component condensation reaction.

A very efficient three-component synthesis of a series of syn α-hydroxy-β-amino esters, obtained in high diastereoselection and yield, was realized starting from an aldehyde, benzylamine, and the ketene silyl acetals derived from Leys lactones. The synthetic protocol was optimized and the above compounds were obtained without the isolation of intermediates. The origin of the observed diastereoselection was investigated through a computational model of the key reaction step.

Isothiazoles. Part VII. An efficient palladium-catalyzed functionalization of 3-amino-4-aryl-isothiazole 1,1-dioxides with organostannanes☆

Abstract The palladium-catalyzed reaction of 5-bromo-3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxide (3) with a variety of vinyl-, aryl-, heteroaryl- and alkynylstannanes 4 provides a general and efficient method for the synthesis of 5-substituted isothiazole 1,1-dioxides 5. Different reaction conditions (catalyst, solvent, temperature) were tested for the coupling. The best results were obtained using toluene at reflux and benzylchlorobis(triphenylphosphine)palladium as catalyst. When organostannanes appeared to be less reactive, prolonged heating resulted in the formation of variable amounts of the reduction product 3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxide (1).

Asymmetric modular synthesis of a semirigid dipeptide mimetic by cascade cycloaddition/ring rearrangement and borohydride reduction.

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments.