Combinatorial libraries primary

First the primary combinatorial library of chiral ligands LI —L5 and chiral activators Al —A5 (Scheme 12) were studied in order to optimize the lead structure of the next generation of chiral ligands and activators.87,89... 

In summary, we have described an efficient and facile solid-phase synthesis of substituted ureas starting from aminomethyl MicroTubes. The synthesis takes place under mild conditions. Taking into account the commercial availability of primary amines, this strategy can be ideally used for the synthesis of large combinatorial libraries. 

As synthetic steps, the Michael additions of nitrogen nucleophiles were followed by nucleophilic substitutions of the chlorine atom with a primary amine and, finally, alkylations of the then secondary amino group with various alkyl bromides were performed just as previously developed for the chloro ester 1-Me in solution (see, e.g. Schemes 25,27,36 etc.). With differently substituted pyra-zoles as Michael addends, different primary amines and alkyl bromides, combinatorial libraries consisting of 8, 24 and 84 compounds were thus successfully prepared in ca. 60% yield and proved by the LC-MS technique to contain all the individual compounds in about equal amounts (Scheme 80) [127]. 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

Computational methods described in this work are tested using a tripeptoid combinatorial library described by Zuckermann et al. (35). These authors described chemical structures of 24 amines used as building blocks for the pep-toid synthesis. The common Markush structure of tripeptoids is shown in Fig. 3 where R1, R2, and R3 are the alkyl portions of primary amines used as building blocks. The structures of the building blocks are shown in Fig. 4 and we followed the abbreviations used in the original publication. 

Most of the affinities of Fabs or scFvs isolated from combinatorial libraries have affinities similar to those of antibodies found in the primary immune response in vivo (Kd 10-6—10 7M), but in vivo, these affinities are improved during affinity... 

Hard filters are the most stringent in-silico filters and are used to shape the property profile of screening or combinatorial libraries and to prune hit lists from primary screening. They are derived from ID and 2D molecular properties (molecular weight, number of H-bond donors/acceptors, number of rotatable bonds, and so forth) and, as is described below, they are commonly used to reduce the number of false positive hits and to favor lead-like or drug-like chemotypes. 

Polymer libraries have recently been the focus of several publications with the aim either to discover novel polymeric materials for a specific application (primary libraries) or to rapidly optimize the properties of known polymers (focused libraries). All the major areas where successful combinatorial approaches to polymer libraries have been reported are covered in the following sections with the help of a specific, recent example and up-to-date referencing. Several other papers dealing with polymer combinatorial libraries can be consulted by the interested reader (80-89). 

At the other extreme if you have no knowledge of the protein structure, no candidate ligands, and the X-ray structure is not yet known then a high throughput screening of primary large scale collections of compounds or combinatorial libraries would be screened. These techniques would use roboticized and miniaturized assays and be done to search for possible binding compounds. 

Figure 7-19. Primary combinatorial library of cbiral ligands (L L ) and chiral activators...

On the basis of the results collected from the primary combinatorial library, we then create the next generation library of diimines (activators) with 12 members... 

All of the aforementioned HPLC purification systems employ detectors other than mass spectrometers as the selection criteria by which peaks are collected. With these systems, however, mass spectrometry is generally employed as a primary structural validation tool. More recently, systems have been described whereby a mass spectrometer has been added to preparative HPLC format to detect compounds of interest for collection. A recent review by Kassel [9] discusses the relative merits of employing MW-triggered versus UV-triggered fraction collection in various environments for the purification of combinatorial libraries. 

In early 1998, a further class of peptoid oligomers appeared [25], when a solid-phase method was developed to synthesize N-substituted P-aminopropionic acid oligomers, termed P-peptoids. Treatment of Wang s resin with acryloyl chloride, followed by Michael addition of primary amines afforded N-substituted P-alanines. A combinatorial library of... 

---