Projects / Molecular structures to targeting tumor cells

New-dicarba analogues of somatostatin with ssts specific activity for radiolabelling


Fondazione Umberto Veronesi

The Somatostatin (SRIF) is a hormone produced by endocrine, neuronal and gastrointestinal cells. Besides, the ability to inhibit the release of growth hormone (GH) numerous studies have also highlighted its remarkable inhibitory effects, endocrine and exocrine secretion, making it a potential drug against diseases such as diabetes type I and II, disorders gastrointestinal and against tumors ipersecretory. The Octreotide 1, synthetic peptide formed by eight amino acids, is the analogue of somatostatin most widely used the clinical practice because it has an improved resistance to enzymatic degradation processes while maintaining the same specific activity. Because of the ease of breakage of the disulfide bridge in 1 for the attack of reducing endogenous enzymes, nucleophilic and basic agents, we designed and prepared more robust dicarba-analogues such as the compound shown in Figure 2,  that retains the characteristic sequence of the Octreotide. 


Octreotide (1) and its first dicarba-analogue (2).

The key reaction in order to obtain such ciclyopeptide derivatives is the ring-closing metathesis (RCM), an intramolecular olefin metathesis-catalyzed by complexes of ruthenium (Grubbs catalysts of first and second generation as well as Hoveyda-Grubbs catalysts), carried out on linear peptides containing in strategic positions residues of L-allylglycine. The solid-phase cyclization reaction was performed by conventional heating or by the Mw technique, depending on the cycle size and on the aminoacid sequence. This latter method gave excellent results especially for 8-mer rings. The conjugation of these structures with chelating agents such as DOTA led to the possibility of using the peptides synthesized by us as radiopharmaceutical  drugs. Unfortunately, in some cases, the introduction of the chelating molecules caused a loss of affinity for specific ssts. Researches are ongoing  to clarify if the loss  of affinity is due only to conformational changes or also to the lipophilicity variation. In order to investigate the influence of lipophilicity and of distance of the chelating agent from the peptide sequence, we are introducing X spacers of different length and polarity between the chelating moiety and the peptide ring.




Structure of dicarba-somatostatin analogs-X-DOTA (3)

Another research line  deals with the introduction of a silicon-Fluoro acceptor on dicarba-octreotide derivatives which are of biologically active in order to obtain, 18F labeled peptides, potential radiopharmaceuticals for PET  technique in oncology.