Synthesis and characterization of linear and cyclic ... - EleA@UniSA

1. Introduction
Chapter 1
“Giunto a questo punto della vita, quale chimico, davanti alla tabella del Sistema Periodico, o agli indici
monumentali del Beilstein o del Landolt, non vi ravvisa sparsi i tristi brandelli, o i trofei, del proprio passato
professionale? Non ha che da sfogliare un qualsiasi trattato, e le memorie sorgono a grappoli: c’è fra noi chi ha
legato il suo destino, indelebilmente, al bromo o al propilene o al gruppo –NCO o all’acido glutammico; ed ogni
studente in chimica, davanti ad un qualsiasi trattato, dovrebbe essere consapevole che in una di quelle pagine, forse in
una sola riga o formula o parola, sta scritto il suo avvenire, in caratteri indecifrabili, ma che diventeranno chiari
: dopo il successo o l’errore o la colpa, la vittoria o la disfatta.
Ogni chimico non più giovane, riaprendo alla pagina > quel medesimo trattato, è percosso
da amore o disgusto, si rallegra o si dispera.”.
3
Da “Il Sistema Periodico”, Primo Levi.
Proteins are vital for essentially every known organism. The development of a deeper understanding
of protein–protein interactions and the design of novel peptides, which selectively interact with proteins
are fields of active research.
One way how nature controls the protein functions within living cells is by regulating protein–
protein interactions. These interactions exist on nearly every level of cellular function which means they
are of key importance for virtually every process in a living organism. Regulation of the protein-protein
interactions plays a crucial role in unicellular and multicellular organisms, including man, and
represents the perfect example of molecular recognition 1 .
Synthetic methods like the solid-phase peptide synthesis (SPPS) developed by B. Merrifield 2 made it
possible to synthesize polypeptides for pharmacological and clinical testing as well as for use as drugs
or in diagnostics.
As a result, different new peptide-based drugs are at present accessible for the treatment of prostate
and breast cancer, as HIV protease inhibitors or as ACE inhibitors to treat hypertension and congestive
heart failures, to mention only few examples 1 .
Unfortunately, these small peptides typically show high conformational flexibility and a low in-vivo
stability which hampers their application as tools in medicinal diagnostics or molecular biology. A
major difficulty in these studies is the conformational flexibility of most peptides and the high
dependence of their conformations on the surrounding environment which often leads to a
conformational equilibrium. The high flexibility of natural polypeptides is due to the multiple
conformations that are energetically possible for each residue of the incorporated amino acids. Every
amino acid has two degrees of conformational freedom, N–Cα (Φ) and Cα–CO (Ψ) resulting in
approximately 9 stable local conformations 1 . For a small peptide with only 40 amino acids in length the
1 A. Grauer, B. König Eur. J. Org. Chem. 2009, 5099–5111.
2 a) R. B. Merrifield, Federation Proc. 1962, 21, 412; b) R. B. Merrifield, J. Am. Chem. Soc. 1964, 86, 2149–2154.