Peptide-like compounds

Garren, K. W., Pyter, R. A., Aqueous solubility properties of a dibasic peptide-like compound, Int. J. Pharm. 63, 167-172 (1990). 

Garrigues et al. [49] characterized two different but partially overlapping P-gp pharmacophores. Initially, they determined affinities and mutual relationships from the changes in P-gp ATPase activity induced by a series of cyclic peptides, peptide-like compounds used alone or in combination. Because verapamil binding to P-gp... 

Peptide-like compounds raise the further significant issue of chirality control. When all the chiral fragments consist of natural amino acids, the chiral sources are natural amino acids themselves. However, when chiral non-natural amino acids are used as bioisosteres of amino acid residues to construct peptide mimetic compounds, the chirality needs to be constructed as efficiently as possible. Multi-step or low-yielding processes resulting from the necessity to control chirality often lead to the potential risk of large amounts of waste and a high environmental burden. 

Interesting approaches to affect intestinal absorption include drug physicochemical modification by either chemical derivatization or the use of delivery agents, low molecular weight peptide-like compounds that form a complex with the permeant. Generally, the transport of... 

The peptide-like compounds (55) have been obtained following reactions between li-phosphorylated 2-pyrrolidinecarboxylie acid,... 

Kemp et al. suggested that cyclic peptide-like compounds could be used to nucleate helix formation by providing the correct... 

Complexation of drugs in the GI tract can occur with the luminal content. Any non-metallic atom, whether free or contained in a neutral molecule, or an ionic compound that can donate an electron pair, may serve as a donor. The acceptor is frequently a metal ion. In general, complexes can be divided into two classes, depending on whether the acceptor component is a metal ion or an organic molecule (Dakas and Takla 1991, Horter and Dressman 1997). Complex formation with components of food, such as milk, can give precipitation of the drug compound and reduce the bioavailability and fraction of the dose absorbed. Complex formation of peptide-like compounds and enzymes in the GI tract lumen has also recently been reported (Sjostrom et al. 1999) and a reduced bioavailability was observed. 

Gstirner and Vogt described isolation and amino acid composition of peptides of Ginseng roots (150, 151) and recently Okuda etal, reported presence of an anti-lipolytic peptide like compound in Red Ginseng (152). Structures of these compounds are still unknown. Kosuge etal. recently isolated the neurotoxin P-N-oxalo-L-a,P-diaminopropionic acid as the hemostatic principle of Sanchi-Ginseng (153). 

This review is focused on peptide-like compounds, however, some alkaloids have been reported from cyanobacteria. The most recent example is nostocarboline (19), which was isolated from cultured cells of the freshwater cyanobacterium Nostoc sp. [51]. This compound is a new quaternary /3-carboline alkaloid. The structure was confirmed by its total synthesis. Strikingly, the alkaloid inhibited butyrylcholinesterase (IC50 13.2 p,M). The activity is comparable to an approved drug for the treatment of Alzheimer s disease. Cyanobacteria are thus possible sources of pharmaceuticals for neurological disorders. 

Nonribosomal polypeptides are peptide-like compounds that are biosynthesized from amino acids by a multifunctional enzyme complex without direct RNA transcription. The penicillins are good examples, but their chemistry is a hit complicated and weTl not discuss their biosynthesis. 

Perhaps the best-known MCR is the Ugi four-(or higher) component condensation (U-4CR) [29]. First reported in 1959, the Ugi-4CR describes the conversion of carbonyl compounds 9-16, amines 9-17, various types of acids 9-19 and isocyanides 9-21, the final product being peptide-like structures 9-24. A rather simplified mechanism of the Ugi-4CR is depicted in Scheme 9.4. 

Bioteehnology produets differ in their method of preparation and potential problems they present in their formulation. Pharmacists involved in compounding with biologically active proteins are interested in their stabilization, formulation, and delivery. Most of the current biotechnology products are proteins, but soon some may be smaller peptide-like molecules. 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

In general, there are many more examples of the reactants available than can be handled in practice and thus selection methods must be used. For example, when designing peptides there are 20 amino acids and hence 20 x 20 or 400 dipeptides 8000 tripeptides 32K tetrapeptides, and so on. When designing libraries of small drug-like compounds, in general there could be tens or even hundreds of possible reactants available for each position of variability. Thus, even when libraries are limited to a single reaction scheme, the numbers of compounds that could potentially be made can be very large. 

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