Reverse-turn mimics

Winningham MJ, Sogah DY. A modular approach to polymer architecture control via catenation of prefabricated biomolecular segments polymers containing parallel /8-sheets templated by a phenoxathiin-based reverse turn mimic. Macromolecules 1997 30 862-876. 

Generic scaffold for peptide reverse turn mimics claimed Libraries based on claimed scaffolds were claimed Biological activity of claimed libraries were claimed... 

In most cases, pyrazino[l,2- ]pyrazines have been synthesized as highly saturated derivatives with the aim of preparing conformationally restricted compounds which mimic the secondary structure of reverse-turn regions of peptides and proteins. The saturated pyrazino[l,2- ]pyrazine 241 was synthesized from readily available starting materials, the key steps being the preparation of the keto amide 239 and subsequent tandem cyclizations from [6+0] atom fragments (Scheme 42) <20000L301>. 

A similar strategy was used to examine the potential role of a reverse turn as a recognition element adjacent to the cleavage site of substrates of HIV protease.197 A series of inhibitors was prepared, the synthesis of which involved the solution coupling of the statine-like transition state mimic to the (3-turn mimetic to provide 46 (Scheme 22). Subsequent sodium in ammonia reduction provided analogue 47. One of the compounds was a reasonably potent inhibitor of protease activity (IC50=2.6 x 10-8 M) (Table 1). 

As a key feature of the TASP approach, the template is designed to direct and reinforce the folding of the covalently attached secondary structure elements in the predetermined tertiary structures (Scheme 1), e.g. a four a-helical bundle. The major purpose of artificial turn-inducing mimics is to constrain, when incorporated at the appropriate location, the peptide chain into a semi-rigid, defined, spatial arrangement. 39 8-(Aminomethyl)-5,6,7,8-tetrahydro-2-naphthoic acid (Amhn) is designed to substitute for the central dipeptide unit of a reverse turn and is prepared in a five-step procedure starting from commercially available 4-phen-ylbutanoic acid 40 (Scheme 3). 

Iqbal and coworkers have reported another approach to cycUc di- and tripeptide mimics constrained with a disubstituted aromatic linker which exploits a free-radical-mediated macrocycHzation [8]. As an example, the tripeptide derivative 8 was promoted to undergo 7-endo ring closure under tin hydride conditions, providing the cyclic peptide 9 in 54% yield (Scheme 5). The reasonable yields obtained for these macrocycHzation processes is proposed by the authors to occur because of preorganization of the acycHc precursors, possibly owing to a reverse turn (y/ turn). 

Arbor, S., and Marshall, G. R. (2008) A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank. J. Comput. Aided Mol. Des. 23, 87-95. 

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... 

Several of the model cyclic peptides used In these studies were designed to mimic regions of polypeptide chains where hydrogen bonded reverse turns are likely to occur CS., i, Ifl), These peptides contain prollne, an imlno acid which has a high frequency of occurrence in turns (JJ), and which is intrinsically interesting... 

A modified carbon paste electrode (CPE) using asolectin, cytochrome c, and cytochrome oxidase were applied for amperometric determination of cyanide [56]. The modified CP matrix mimics a biological membrane environment. The sensor, polarized at —0.15 V versus Ag/AgCl, generates the reduced form of cytochrome c, which in turn is oxidized by the enzyme cytochrome oxidase. The resulting current is related to the enzyme activity and is depressed by inhibitors of cytochrome oxidase such as cyanide. Concentrations of cyanide as low as 0.5 pM can be measured with half-maximal response at about 12 pM. The inhibition is reversible and reproducible (RSD = 4%), allowing cyanide determination for more than 2 months using the same probe. Possible use of this biosensor in flow systems was illustrated. 

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