Natural and Synthetic Oligoarylamides: Privileged Structures for Medical Applications

Abstract

The term “privileged structure” refers to a single molecular substructure or scaffold that can serve as a starting point for high‐affinity ligands for more than one receptor type. In this report, a hitherto overlooked group of privileged substructures is addressed, namely aromatic oligoamides, for which there are natural models in the form of cystobactamids, albicidin, distamycin A, netropsin, and others. The aromatic and heteroaromatic core, together with a flexible selection of substituents, form conformationally well‐defined scaffolds capable of specifically binding to conformationally well‐defined regions of biomacromolecules such as helices in proteins or DNA often by acting as helices mimics themselves. As such, these aromatic oligoamides have already been employed to inhibit protein–protein and nucleic acid–protein interactions. This article is the first to bring together the scattered knowledge about aromatic oligoamides in connection with biomedical applications.

Display‐Selektion eines Foldamer‐Peptid‐Makrozyklus‐Hybriden

“…Außerdem verleiht sie dem Peptid Resistenz gegen proteolytischen Abbau [12] . Darüber hinaus haben AOF s selbst das Potenzial, direkt mit Proteinen zu interagieren, [13] und sie existieren als Naturprodukte [14] . Es war daher ein logischer nächster Schritt, die ribosomale Translation nicht nur mit der Herstellung eines AOF ‐Peptid‐Makrozyklus, sondern mit einer ganzen DNA‐kodierten Bibliothek solcher Makrozyklen zu erproben.…”

Improvement of the antimicrobial potency, pharmacokinetic and pharmacodynamic properties of albicidin by incorporation of nitrogen atoms

“…As the D-E-F fragment of the C-terminal part of albicidin shares its main structural features with aromatic oligoamides (AOA), 42 it is to be expected that albicidin might show coordination patterns similar with AOA and its geometrical structure can be analysed in in the same way. It has been shown that the incorporation of hydrogen acceptors, such as alkoxy substituents or a heterocyclic nitrogen into the aromatic rings of the AOA scaffold results in the formation of intramolecular hydrogen bonds (IMHB), which are responsible for conformational restrictions leading to a number of molecular architectures.…”

Transcriptional Regulation of Congocidine (Netropsin) Biosynthesis and Resistance

“…Pyrrolamides are characterized by the presence of 4-aminopyrrole-2-carboxylate groups linked by amide bonds. They exhibit a large range of biological activities (antiviral, antimicrobial or anthelmintic activities), mainly due to their ability to bind into the minor groove of the DNA (10). Indeed, congocidine and distamycin have been extensively studied for the specificity of their binding to DNA.…”

“…Physical studies (e. g. X-ray structure determination and circular dichroism measurements) have shown that they exhibit a marked preference for A/T rich DNA regions (11,12). Many analogs and hybrids of congocidine and distamycin have been synthesized chemically, in attempts to modify or increase the sequence specificity of the DNA binding for gene expression regulation applications (10), or to create new nontoxic antimicrobial molecules (13).…”