______________________________________________________________Abstract
Naturally occurring peptides and proteins, owing to their different
biological activities, are a class of compounds even more important both
for medicinal chemistry and pharmacological research. However, because
of their instability and limited absorption by living organisms often
chemical-structural modifications are needed in order to increase the
biological effects. Among the emerging areas of the research concerning
the drug design the synthesis of peptidomimetics deserves a lot of efforts,
and peptide sequences in which natural amino acids have been replaced
with non proteinogenic structures are always more frequent, with the aim to
obtain compounds displaying the same therapeutic effects of natural
peptides, together with the highest metabolic stability.
Therefore this research was directed towards new methodologies able to
give rise to conformationally constrained mimetics of peptide systems,
having more manageable metabolic stability and pharmacokinetic
properties with respect to the corresponding natural peptides. In particular,
the synthetic work concerned preparation of conformationally constrained
isosteres of -homoserine, an RGDG sequence and a tripeptide FEG,
starting from a common precursor, a modified Baylis-Hillman adduct.
X
EtOOC
COOMe
X= OTBDMS
X= NHCOCCl3
At first this molecule allowed to prepare by a number of synthetic
pathways four functionally protected isosteres of -homoserine through
a stereodivergent approach.
1
______________________________________________________________Abstract
H
H
tBocN
tBocN
OH
O
OH
N
O
N
H
H
H
H
tBocN
tBocN
OH
OH
O
O
N
N
H
H
H
t-BocN
H
COOMe
t-BocN
COOMe
O
N was further converted into an aspartic acid isostere,
The same substrate
O
N
which gave at first a dipeptide DG isostere and then an analogous of a
COOBn
RGDG sequence.
OCH3
NHZ
ZN
O
N
H
H
N
N
t-BocHN
H
COOMe
O
O
N
COOBn
Eventually, the same starting material afforded, through the
homologation of the C-4 carboxylic functionality of the pirrolidin-2one, a conformationally constrained mimetic of dipeptide EG, which
was subsequently converted into a constrained analogous of tripeptide
FEG.
2
______________________________________________________________Abstract
H
N
t-BocN
H
COOCH3
O
O
N
COOBn
In conclusion, we devised to synthesize these molecules owing to
important biological effects of the corresponding native peptides (e.g.
proapoptotic activity for homoserine, anti-angiogenic, tumor targeting
and drug delivery for RGD peptide, antiinflammatory for peptide FEG).
The stereoselection and the high chemical yield of the processes we
carried out allow to consider these mimetics useful for a broad spectrum
of applications both for medicinal chemistry and for pharmacological
purposes directed to peptide-based therapy.
Particularly, it has been carried out in vitro morpho-functional studies
on substrata with RGD grafting in order to underline as the RGDmediate cellular adhesion represents an important pre-requisite for the
maintenance of a membrane dynamic that favours the therapeutic
molecules absorption from the extracellular environment.
Therefore, these data complete the information gotten by the RGD
synthetic process, showing multiple functional values of such peptide
but all finalize to the activation and the amplification of the cellmicroenvironment interaction, essential for a therapeutic and/or
diagnostic use of this class of molecules.
3