Synthesis, chemical peptidomimetics

Zuckermann RN. The chemical synthesis of peptidomimetics. Curr. Opin. Struct. Biol. 1993 3 580-584. 

Basso, A., WrubI, F. MCR approach to synthesis of peptidomimetic libraries. Speciality Chemicals Magazine 2003, 23, 28-30. 

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

Nilsson BL, Soellner MB, Raines RT. Chemical synthesis of proteins. Annu. Rev. Biophys. Biomol. Struct. 2005 34 91-118. Pegoraro L, Moroder L. Synthesis of lipopeptides. In Houben-Weyl Methods of Organic Chemistry, Synthesis of Peptides and Peptidomimetics. Goodman M, Felix A, Moroder L, Toniolo C, eds. 2003. Thieme, Stuttgart, Germany. 

In both cases, amino acids that can modulate chemical-physical properties such as lipo-philicity (like 11, present in saquinavir and nelfmavir), can produce supplementary bonds (like 12 and 13 [42]), or can induce stereochemical constraint (like 14 [43]) are frequently used (Fig. 15). The design and synthesis of conformationally constrained amino acids as scaffolds for peptidomimetics synthesis, has been recently reviewed by Hanessian [44]. 

The cellular and in vivo use of natural phosphoamino acid-containing peptides has severe limitations because, in addition to the poor chemical stability of the 0-phosphate group, they are subjected to dephosphorylation by phosphatases and are poorly absorbed into cells. These circumstances and the potential therapeutic use of compounds containing enzymatically and chemically stable phosphoamino acid isosteres have motivated the synthesis of phosphoamino mimetics. Figure 20 shows some selected examples of phosphotyrosine (44 [175-177], 45 [176], 46 [178], 47 [179], 48-49 [177], 50 [180], 51 [177], 52 [181], 53 [182], 54 [183], 55-56 [184,185], 57 [186]), phosphoserine (58 [187], 59 [188], 60 [189,190], and phosphothreonine (61 [191]) mimetics. These building blocks have been incorporated into peptides and peptidomimetics by solid-phase synthesis using standard procedures [175,179,182,183,189,192-198]. 

Yan LZ, Dawson PE (2001) Synthesis of peptides and proteins without cysteine residues by native chemical ligation combined with desulfurization. J Am Chem Soc 123(4) 526-533 Yin H, Frederick KK, Liu D et al. (2006) Arylamide derivatives as peptidomimetic inhibitors of calmodulin. Org Lett 8(2) 223-225... 

---