Linear peptides, peptidomimetic

Linear peptides and peptidomimetics have been extensively used and will continue to be employed as starting materials for the generation of heterocyclic compounds on the solid phase. As will be shown, many different structures have been prepared starting from dipeptidomimetics. 

Besides the use of novel fiinctionahty that is beyond rational design by synthetic chemists, nature is unsurpassed at the display of chemical information in three-dimensional space. For example, despite intensive efforts, there is no standard algorithm for translating a linear peptide into a small-molecule peptidomimetic. Meanwhile, numerous natural scaffolds perform this task efficiently, as in the opium alkaloids conformational mimicry of the enkephaUns. We will never know what revolutionary new scaffolds and pharmacophores will be lost if natural product screening is discontinued. 

Figure 4.21 Examples of peptidomimetic HDAC inhibitors, together with a linear peptide 63 used as a control for 62.

The first series of HIV-1 PR inhibitors, referred to as peptidomimetic inhibitors, are transition state mimics that resemble peptide substrates. They are relatively flexible, linear molecules with a well-defined backbone from which hydrophobic groups are projected into four or more of the subsites of the HIV-1 PR active site. The inhibitors function by creating a hydrogen bond network with a tetra-coordinated structural water molecule that is tightly bound between the inhibitor and the flaps. Inhibition is also depended upon critical interactions between the catalytic aspartates and the inhibitor [27]. 

A novel concept for the synthesis of macrocyclic peptidomimetics 262, which incorporate heteroaromatic units, was reported (Scheme 39). This method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[l,3,5]triazines. The scope of this novel solid-phase approach was evaluated systematically by means of the SPOT-synthesis methodology on planar cellulose membranes <2000JC0361>. 

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