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Research Unit coordinated by Prof. Ermanno Valoti  

Academic Staff: Prof. E. Valoti, Prof. M. Pallavicini, Dr. C. Bolchi, Dr. L. Fumagalli

Research collaborators: Dr. Chiodini G. (PhD)

 

The group is active in different research areas of medicinal chemistry. Its expertises range from design, preparation and physicochemical analysis of bioactive molecules, particularly in unichiral form, to computational chemistry and structure activity relationships analysis.

1) α1-Adrenoceptorsubtypesand5-HT1Areceptorligands

The studies are performed in collaboration with Prof. Alberto Chiarini research team (Dipartimento di Scienze Farmaceutiche, Università di Bologna) and with Marco Gobbi (Istituto di Ricerche Farmacologiche “Mario Negri”, Milano). Starting from the nineties, a large variety of analogues of well-known α1-adrenoceptor antagonist WB4101 have been designed, synthesized and characterized for their affinity at the three α1 adrenoceptor subtypes and at the 5-HT1A receptor allowing some distinctive aspects of the interactions with each of these to be highlighted. More recently, the results of these binding studies led to novel, very potent α1 adrenoceptor antagonists with high subtype selectivity.

2) Neuronal nicotinic receptor ligands

The studies are conducted in collaboration with Prof. Francesco Clementi and Cecilia Gotti research team (Dipartimento di Farmacologia Medica, Università di Milano). This scientific partnership began at the end of the nineties, leading to the discovery, in 1998, of the potent and highly selective antagonistic activity of some stylbenoxyethylammonium compounds at the α7 neuronal nicotinic receptor. After 2000, the investigations focused on α4β2 nicotinic receptor, the major brain subtype, searching for selective ligands with agonistic activity. Initially applying a ligand-based approach and successively using also information deriving from receptor modelling, new ligands (pyrrolidinylmethoxyimines, pyrrolidinylbenzodioxanes and substituted pyrrolidinylbenzodioxanes) with from submicromolar to nanomolar α4β2 affinity were developed.

3) Farnesyltransferase inhibitors

Inhibition of farnesyltransferase (FTase), an enzyme involved in cell proliferation, is intensively investigated due to the therapeutic potential against cancer, atherosclerosis and protozoa infections. Recently, this group undertook to develop new peptidomimetic inhibitors, whose FTase inhibiting activity and antiproliferative effect are studied by Prof. Alberto Corsini research team (Dipartimento di Scienze Farmacologiche, Università di Milano). The minimum length oligopeptide accepted by FTase as co-substrate for in vitro reaction has been used as a template to design new molecules, some of which show good activity in both enzimatic and cellular tests.

4) Analytical and preparative stereotechnologies

Chirality and chirality preference are continuously experienced in nature, particularly in life processes, and medicinal chemistry, which studies how chemical agents, often chiral themselves, interact with living matter, cannot ignore such constitutive features. Many questions, both theoretical and practical, as to chirality ask for answers or innovative solutions and discoveries or advancements in this area are regarded with great interest. Resolving enantiomeric pairs on a preparative or analytical scale by a novel procedure or an original methodology, racemizing an enantiomer by the simplest way, investigating the nature and the behaviour of stereoisomeric systems are often challenging problems, which require very different approaches (asymmetric chemical or biological catalysis, resolutions) and technologies (spectroscopy, thermal analysis, electrophoresis, x-ray diffraction, chromatography). In the last twenty years, expertise and know-how of this team in stereotechnologies are increased and refined. The enzymatic resolution of glycerol carbonate, the classical resolution of solketal, arylalkylamines and arylpropionic acids, the entrainment resolution of carnitinamide and 5-hydroxymethyloxazolidinone, stereospecific syntheses of naproxene and esermethol, and the characterization of a number of stereoisomeric mixtures are the main results obtained to now and new researches are in progress.

 

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