Macrocyclic mimetics

Previous reviews on peptidomimetics have addressed pseudopeptides (11), macrocyclic mimetics (13), natural product mimetics (14), cyclic protease inhibitors (15), mimetics for receptor ligands (16-22), and earlier general overviews (23-29). This review will focus on the design process itself. Novel peptidomimetics in which the structural relationship between parent peptide and the peptidomimetic has been established by biophysical methods are used to clarify the principles. Successful approaches are highlighted to illustrate how these concepts are currently used. 

Among many different complexes that have been synthesized in attempt to mimic the structure and/or functionality of SODs (16-22), the most active SOD mimetics known to date are seven-coordinate Mn(II) complexes with macrocyclic ligands derived from C-substituted pentaazacyclopentadecane [15]aneNs and its pyridine derivative (Scheme 4) (12d,16a,23-25). Some of them possess SOD activity that exceeds the one of native mitochondrial MnSOD, and are the first SOD mimetics which entered clinical trials (12d,16a,23,26-28). A few Fe(III) complexes with the same type of ligands have also been studied and they are one of the best iron-based SOD catalysts (18). It should be stressed that the decomposition of superoxide catalyzed by these complexes has been quantified by direct stopped-fiow method, in the presence of a substantial superoxide excess over catalyst, as a reliable method for determining true SOD activity (29). 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

Kazmaier and coworker described a simple approach to several cyclic peptido-mimetics containing a W-alkylated amino acid via Ugi reaction and a RCM (Scheme 19) [86, 87]. W-terminally protected Aloe amino acids c and aUyl isocyanides d were used in an Ugi-4CR to give the linear precursors e in good yields (72-96%) these were cyclized to the macrocycles f by a subsequent RCM. 

The important difference between linear and cyclic peptides is the reduced conformational flexibility imposed by the cyclization. 14,151 Cyclic peptides have, therefore, been under intense investigation with respect to their conformational preferences 30,31 and their different turn motifs, e.g. reverse turns. 32 35 To differentiate between the structural influences of the numerous sequence elements the following special concepts have been described 161 (1) Global constraints are structural characteristics that restrict the whole molecule, e.g. the macrocyclic structure of the peptide framework and (2) local constraints comprise a large number of structure-inducing building blocks, such as proline, D-amino acids, and turn mimetics. 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

Scheme 25. Solid-phase synthesis of macrocyclic /3-turn mimetics.

Several potent inhibitors of fibrinogen binding to gpIIb/IIIa are now known, and some have proven to be effective antithrombotic agents. These inhibitors tend either to be small cyclic peptide mimetics, in which the conformation of an RGD sequence is constrained by macrocyclization, or they are non-peptidic molecules containing functional group mimetics of the Arg and Asp side chains, held in the correct geometry for interaction with the receptor. Examples of both classes are shown in... 

Phan, J., Shi, Z-D., Burke, T.R., Jr., and Waugh, D.S. (2005) Crsytal structures of a high-affinity macrocyclic peptide mimetic complex with the Grb2 SH2 domain. J.Mol. Biol. 353,104-115. 

A variety of macrocyclic natural products, either peptides or peptide-mimetic structures with HD AC inhibitory activity and promising pharmacological effects, have been reported. Some of them are shown in Fig. 5 for illustration for instance, romidepsin 9 (FK228) exhibits excellent class I inhibitory activity and has recently been approved by the FDA for the treatment of cutaneous T-cell lymphoma patients [58, 59]. Similarly, the marine natural product largazole 10 that demonstrates potent antiproliferative activity [60] and HC-toxin 11, a fungal metabolite with immunosuppressant activity, have been investigated as cytostatic agents [61, 62]. 

Vanadium compounds, mainly square pyramidal complexes of the type [0=V(0—R—0)2], act as insulin mimetics with potential in diabetes control if toxicity issues can be overcome one is in use as an orally-administered agent in animals. A pentagonal bipyramidal complex of manganese(II), CMnC A ], where N5 is a pentaaza macrocycle with four amine nitrogen donors and one pyridine nitrogen donor, acts as a... 

While this monocyclic reverse-turn template clearly mimics the backbone conformation and side-chain presentations of p- and "y-tums quite well, one concern with such a large macrocycle is that the relatively flexible peptide backbone conformations are strongly influenced by the side-chain-side-chain interactions, as investigated by NMR solution structure (Fig. 29.11). ° We therefore needed a new type of turn mimetic bearing a constrained and rigid skeleton which could potentially enhance binding and/or improve bioavailability. Based on the conformational analyses of several heterobicyclic systems, we envisioned... 

The first Grb2 SH2 domain binding ligands derived from carboxamido-based macrocyclization of the pTyr mimetic P-position (522) have been presented (Figure 105a). " ... 

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