Francesco Lucchesini

Synthesis of 2,6-disubstituted benzylamine derivatives as reversible selective inhibitors of copper amine oxidases

In order to obtain substrate-like inhibitors of copper amine oxidases (CAOs), a class of enzymes involved in important cellular processes as well as in crosslinking of elastin and collagen and removal of biogenic primary amines, we synthesized a set of benzylamine derivatives properly substituted at positions 2 and 6 and studied their biological activity towards some members of CAOs. With benzylamines 6, 7, 8 containing linear alkoxy groups we obtained reversible inhibitors of benzylamine oxidase (BAO), very active and selective toward diamine oxidase (DAO), lysyl oxidase (LO) and monoamine oxidase B (MAO B) characterized by a certain toxicity consequent to the crossing of the brain barrier. Poorly toxic, up to very active, reversible inhibitors of BAO, very selective toward DAO, LO and MAO B, were obtained with benzylamines 10, 11, 12 containing hydrophilic ω-hydroxyalkoxy groups. With benzylamines 13, 14, 15, containing linear alkyl groups endowed with steric, but not conjugative effects for the absence of properly positioned oxygen atoms, we synthesized moderately active inhibitors of BAO reversible and selective toward DAO, LO and MAO B. The cross examination of the entire biological data brought us to the conclusion that the bioactive synthesized compounds most likely exert their physiological role of reversible inhibitors in consequence of the formation of a plurality of hydrogen bonds or hydrophobic non-covalent interactions with proper sites in the protein. Accordingly, the reported inhibitors may be considered as a set of research tools for general biological studies and the formation of enzyme complexes useful for X-ray structure determinations aimed at the design of more sophisticated inhibitors to always better modulate the protein activity without important side effects.

Synthesis of Model Molecules and NMR Analysis of Polymeric Reagents Based on Propane‐1,3‐dithiol and 1,3‐Dithiane Systems

Purposely synthesized model compounds, one- and two-dimensional NMR spectra and simulations are used for a full 1H and 13C NMR spectroscopic investigation of soluble copolymeric reagents for supported organic syntheses containing (1,3-propanediyl)bis(benzenesulfonate), (1,3-propanediyl)bis(thioacetate), propane-1,3-dithiol, and 1,3-dithiane functions. The collected NMR spectroscopic data confirm the possibility of rapid and accurate assessments of preparations and applications of the newly prepared copolymeric reagents, without resorting to special equipment.

Synthesis and NMR investigation of styrene glycopolymers containing D-galactose units functionalized with 4-(4-hydroxybutoxy)benzylamine residues

As a part of a work aimed at the synthesis of properly functionalized nanostructured glycopolymers suitable for interaction studies with copper amine oxidases, D-galactose was transformed through a six step sequence into the monomer N-(4-vinylbenzoyl)-6-amino-6-deoxy-D-galactose (1) which was converted into nanostructured crosslinked polymers (R1) by radical precipitation polymerization and into linear polymers (P1) by solution polymerization. The linear polymers were useful models for setting up glycosylation reactions to introduce N-trifluoroacetyl-4-(4-hydroxybutoxy)benzylamine residues in the presence of camphor sulfonic acid as the catalyst and to extend them to the nanostructured systems. The advancement of the glycosylation reaction was performed through the synthesis and glycosylation of N-benzoyl-6-amino-6-deoxy-D-galactose (9) as the model molecule for accurate NMR investigations. The removal of the trifluoroacetyl protecting group, unexpectedly stable, in glycosylated P1 and R1 was achieved with sodium borohydride.

Synthesis, glycosylation and NMR characterization of linear peracetylated D-galactose glycopolymers

The glycosylation of D-galactose glycopolymers to produce functionalized polymers expected to be bioactive as substrates or inhibitors of enzymes of the copper amine oxidase class (CAOs, EC 1.4.3.6), attained previously with an unpractical, but significant process requesting a large excess of glycosyl acceptor, has now been achieved with a method based on the use of peracetylated D-galactose moieties, in the presence of SnCl4 or BF3·Et2O as promoters, which employs glycosyl donors in nearly stoichiometric ratio with the desired glycosyl acceptor. After the synthesis of an appropriate model molecule acting as a guide, the new method was set up with extensive NMR investigations on the same model molecule and soluble polymeric reagents and products, performing a full rationalization of the chemical behavior of the various α and β pyranose and furanose forms of D-galactose residues. Glycosylated systems containing functionalities protected with trifluoroacetyl and acetyl groups were fully deprotected in one step through a reduction procedure with NaBH4.