Macrocyclic peptides

Adamantane can be used to construct peptidic scaffolding and synthesis of artificial proteins. It has been introduced into different types of synthetic peptidic macrocycles, which are useful tools in peptide chemistry and stereochemistry studies and have many other applications as well. Introduction of amino acid-functionalized adamantane to the DNA nanostmctures might lead to construction of DNA-adamantane-amino acid nanostmctures with desirable stiffness and integrity. Diamondoids can be employed to constmct molecular rods, cages, and containers and also for utilization in different methods of self-assembly. In fact, through the development of self-assembly approaches and utilization of diamondoids in these processes, it would be possible to design and constmct novel nanostmctures for effective and specific carriers for each dmg. 

Figure 1.11 Covalent capture of peptide macrocycle dimer (Ghadiri).

In order to increase structural diversity and to create a polar domain in the cage-like interior of these steroid/peptide macrocycles, dihydroxylated diacid 127 was synthesized in two steps from cholic acid (126) and reacted with diisonitrile 110, paraformaldehyde, and isopropylamine to form macrocycle 128 and its head-head isomer (Scheme 26). 

Fig. 6 Oxazole-peptide macrocycle libraries targeting G-quadruplex recognition...

Jantos K, Rodriguez R, Ladame S, Shirude PS, Balasubramanian S (2006) Oxazole-based peptide macrocycles a new class of G-quadruplex binding ligands. J Am Chem Soc 128 13662-13663... 

Peptidelike macrocyclic antibiotics of dimeric and trimeric form are often found, an example being echinomycin A (quinomycin A) produced by Streptomyces echinatus from the soil of Cuanza (Angola). The complete structure of a large peptide macrocycle bearing two 2-quinoxalinyl substituents has been elucidated by Prelog and co-workers.183... 

Using 1,1 -ferrocenyldicarbonyl chloride, it should also be possible to prepare polypeptide conjugates in which the Fc group is part of the polymer backbone and linked to the polypeptide through amide linkages. Han and co-workers were able to prepare l,l -ferrocenophane derivatives 57 as well as cyclodimers 58 and macrocyclic compounds from 14 and various cysteine derivatives (Scheme 12.13).82 Presumably, a nondefined polymer is also formed under the reaction conditions. This reaction is akin to the reaction leading to the formation of other Fc-peptide macrocycles discussed earlier (see Scheme 12.5, and Figures 12.5 and 12.6). 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

White CJ, Yudin AK (2011) Confcanporary strategies for peptide macrocyclization. Nat Chem 3 509-524... 

The Hantzsch reaction has also been utilized in the combinatorial synthesis of cyclic peptidomimetics 13 (14ACSCS001), peptide macrocycles 14 (14ACSCS71),oxazole-thiazole bis-heterocyclic compounds (14ACSCS39) (structures not shown). 

Byk, G., Cohen-Oana, M. and Reichman, D. (2006) Fast and versatile microwave-assisted intramolecular Heck reaction in peptide macrocyclization using microwave energy. Biopolymers, 84, 274-82. 

DNA thiol-disulfide exchange 5 oxazole-peptide macrocycles [64]... 

The movement of a human being swimming has been reproduced in a nanomachine capable of unidirectional, four-state switching cycles that are similar to the movement of a breaststroke swimmer. The nanomachine consists in a torso and two foldable arms (Fig. 11.7). The base is a peptidic, macrocyclic scaffold that controls the direction of the movement. The arms are rotated around one hinge and are stretched and folded by another hinge. The machine is moved by alternating addition of chemicals (complexation of a bipyridine by copper ions) and irradiation (isomerization of the azo function) [20]. 

Scheme 17 Synthesis of peptide macrocycles by cyclization of unprotected linear peptides with the KAHA ligation...

Sato K, Itoh Y, Aida T (2011) Columnarly assembled liquid-crystalline peptidic macrocycles unidirectionally orientable over a large area by an electric field. J Am Chem Soc 133 (35) 13767-13769. doi 10.1021/ja203894r... 

A series of peptidic macrocycles has been published by researehers from Harvard and Stony Brook University who reported highly specific, bisubstrate-competitive proto-oncogene tyrosine protein kinase Src inhibitors... 

Independently, the MacroFinder technology platform was developed. This approach is based on non-peptidic macrocycles in the molecular weight range of 400-800 Da and was developed by Polyphor. Macrocycles of ring... 

Two non-peptidic macrocyclic inhibitors of the ETa receptor have also been described. The bromotyrosine-derived macrolactam 34-sulfatobastadin 13 (33, Figure 8.13), isolated from the sponge lanthella sp., weakly inhibits the binding of [ I]-ET-1 to the ETa receptor with an IC50 of 39 pM. The polyketide (—)-kendomycin (34, TAN-2162, Figure 8.13) is a moderately potent inhibitor of both endothelin receptors (ETa IC5o = 11.5 pM ETb ICso = 2.9 pM), isolated from Streptomyces sp AL-71389. ... 

As described in Section 11.7.1, palladium (0) chemistry has been found particularly well-suited for constructing macrocyclic structures and, hence, applications for libraries have also been pursued. Indeed, as already noted, one of the first macrocyclic library efforts actually used the Heck reaction for solid phase construction of small collections of 20- to 24-membered semi-peptidic macrocycles (299, Figure 11.26, site of ring closure and chemistry indicated). In addition, modest-sized libraries of RGD mimic macrocycles (300) ° and macrosphelide analogues (301) were prepared using palladium-catalysed cyclocarbonylation on resin. This particular method proved to be tolerant of a variety of functional groups, including halides, ethers, ketones and esters. 

Cyclization, leading to Gly/Lys-containing peptide macrocycles, has been investigated with a number of coupling reagents. Among them DEPC Diethyl Phosphoro-cyanidate), DPPA, and BOP are the most effective ones, giving near-quantitative yields. 

---