Synthesis of new compounds with specific
biological activities. We obtained a library of new
beta-lactams sustituted with polyphenolic residue that we proved to
be inhibitors of HLE, MMP-2 and MMP-9, thrombin and few of them
showed interesting antibacterial activity. In a research dedicated
to molecular targets of cancer desease, we designed and synthesized
a new family of beta-lactams with a specific inhibitory
activity against HDAC6 and HADC8.
Biocatalysis. We are studying application of
enzymes to the synthesis of fine-chemicals. In particular ,we
used a modified Phenylalanine Dehydrogenase for the synthesis
of non-natural aminoacids, and the Horse Liver Alcohol
Dehydrogenase in a dynamic kinetic resolution process for the
synthesis of enantiopure arylpropanols interesting inetermetiates
in the synthesis of Profens , an important class of
antiinflammatory drugs. We are currently studying the use of
lipases in the enantioselective synthesis of beta-lactams and
beta-amminoacids and the use of Laccases in oxidation reactions.
Since their introduction in therapy, beta-lactams proved to be
chemotherapeutics of incomparable effectiveness, conjugating a
broad spectrum of activity with low toxicity. Beta-Lactams are a
large class of antibiotics characterized by the presence of the
azetidin-2-one ring, which is the core of the biological activity,
and differentiated by side chains, unsaturations, heteroatoms and
in many cases, by the presence of another five- or six-membered
ring. To complete and increase the importance of the beta-lactams,
recently “non-classical” bicyclic and monocyclic beta-lactam
substrates with different biological activity have appeared in the
literature. For instance beta-lactams are inhibitors of serine
dependent enzyme (beta-lactamases, HLE, citomegalovirus proteases),
matrix-metallo protease and they are even apoptosis inductors.
Beta-lactams are enzymatic inhibitors with a wide range of
biological activity towards significant human pathologies. We
recently developed the synthesis of new monocyclic beta-lactam
derivatives, 4-alkyliden-azetidinones, characterized by a
carbon-carbon double bond on the C-4 position of the azetidinone
ring which confers an enhanced reactivity towards ring opening
reactions by serine dependent enzyme. Our synthetic protocol can be
further modified to obtain a small library of
4-alkylidene-derivatives. 4-Alkylidene-betalactams were
functionalized on the side chain with several substitutions. In
particular a series of compounds combining the beta-lactam and
polyphenol scaffold (galloyl moiety) have been prepared and
evaluated for inhibition of human leukocyte elastase (HLE) a very
potent degradative weapon released by inflammatory cells, and
mediator of some severe pathologies such as pulmonary emphysema.
The design of these compounds has been based on the
“overlapping-type” strategy where two pharmacophores are linked in
a single molecule. The most powerful compound against elastase was
an N-galloyl-4-alkyliden beta-lactam with an IC50 of 0.5
microM. This N-galloyl-beta-lactam derivative inhibits the LE
activity with a Ki of 0.7microM. Without affecting chemotactic
response and viability of polymorphonuclear (PMN) leukocytes, the
compound efficiently restrains their chemoinvasion (IC50 of 1,2
microM) blocking the LE-triggered activation of pro-MMP-9,
instrumental to extravasation. Daily i.p. injection of compound
enhances resolution in a pulmonary inflammation model,
significantly reducing consequent fibrosis. These results indicate
that the new beta-lactam is a potent anti-inflammatory compound
with therapeutic potential. Other 4-alkyliden-beta-lactams
functionalized with N-acyl moieties enhances the potency of parent
C-4 saturated compounds as inhibitors of blood aggregation process
mediated by Thrombin. We demostrated even the efficiency of some
polyphenolic-4-alkyliden beta-lactams agaist methicillin resistant
and sensible Stapphilococcus Aureus strains (MRSA and MSSA). We are
now working in a project on the synthesis of
N-thiomethyl-beta-lactams as new antibacterial agents against MRSA
from clinical isolates from cystic fibrosis patients. In a
collaboration with the pharmaceutical company Sigma-Tau we designed
and developed the synthesis of a new family of beta-lactam
compounds which have a significant and specific inhibitory activity
against Histones such as HDAC6 and HDAC8.
We are currently involved in projects on the application of
enzymes in the synthesis of enantiopure molecules with significant
biological activities.Our interest in use of enzyme in the
synthesis of fine-chemicals was addressed to a modified
Phenylalanine Dehydrogenase for the synthesis of non-natural
aminoacids, and the application of the Horse Liver Alcohol
Dehydrogesa for the synthesis of enantiopure arylpropanols,
interesting intermediates in the synthesis of Profens, an important
class of non-steroidal antiinflammatory drugs. In collaboration
with University college of Dublin we are working on the
immobilization of a dehydrogenase obtained from an engeenered
HLADH.
We have several active collaborations with national and
international collegues and company.
