DESIGN AND SYNTHESIS OF NOVEL BIOACTIVE PEPTIDES AND PEPTIDOMIMETICS

Nowadays there’s a growing interest in biologically active peptides for the development of new therapeutics; however in some cases, they could not directly use as drugs, due to their inherent limitations, such as rapid metabolism and low oral activity. As a result, peptides are modified into peptidomimetics with specific characteristics, in a rational design. The present PhD project is focused on the synthesis of several peptides and peptidomimetics, structurally different and presenting individual features, properties, targets and pharmaceutical applications. In particular, two are the research studies we’ve developed during the three years, these are the design of novel Carnosine-like derivatives and of new Farnesyl Transferase Inhibitors (FTIs). Concerning the first topic, we investigated how Carnosine (β-alanyl-L-histidine) structural changes influence its role as scavenger of HNE (4-hydroxy-trans-2,3-nonenal) and other toxic aldehydes. For this reason we modified the carnosine structure firstly replacing the Hystidinil- portion with different aromatic system, secondly substituting the β-alanyl portion with ten different amino acids, chosen in order to cover exhaustively the available chemical space. Finally we rigidified the whole structure, inserting a 2-oxazolidinone; the entire compound underwent biological evaluation, testing their ability to quench HNE. As a result, some of the twenty dipeptides showed impressing scavenging activities and great selectivity towards toxic aldehydes, suggesting us that they can represent truly promising candidates for the design of improved carnosine derivatives. Regarding the second subject, we designed, synthesized and tested several peptidomimetics of the CAAX box, where CAAX is the sequence Cysteine-Valine-Isoleucine-Methionine, able to block the farnesylation of RAS proteins and therefore cell proliferation. The design started from a nanomolar range FTI, previously synthesized by our group, where the central dipeptide (AA) is replaced with a 4-amino-2-o-tolylbenzoyl spacer and the Cysteine (C) with the residue 2-amino-4-thiazolylacetyl. The synthesis of the novel FTIs followed two separate approaches; at first we kept the aromatic spacer and modified the N-terminal residue with other heterocycles; the unimproved antiproliferative activity suggested us to apply other kind of modification. Therefore we replaced the o-tolyl with six heteroaromatic residues, in addition the synthesized compounds presented, as N- terminal residue, the 2-amino-4-thiazolylacetyl itself or the 1,4-benzodioxan-2-ylmethyl or the 1,4-benzodioxan-2-ylformyl. In all the three series of compounds, the 2-thienyl, 1-naphtyl and the 3-furanyl derivatives showed the highest FTase inhibition, at low micromolar level. Taken together, our biological activities provide interesting results, confirming that peptides and peptidomimetics should be employed as therapeutics.