Solid-phase combinatorial methods

The selected signature libraries could be obtained by using Mix and Split solid phase combinatorial method [62] or Pre-mix method [63-65] both allow to rapidly synthesize thousands of combinations of molecules. 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

Other fields using short monolithic units are solid phase synthesis and combinatorial chemistry. Hird et al. [102] predicted that having a single polymer particulate block of porous polymer or monolith would allow the optimization of automation in the field of solid phase (combinatorial) synthesis. They have developed a method for the preparation of monolithic rods, which were then cut into discs of 1.0 to 2.5 mm thickness and used for solid phase synthesis. They... 

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... 

The amide ring-closure method has also been used in a solid-phase combinatorial synthesis of inhibitors of poly(ADP-ribose)polymerase (PARP-1). The penultimate intermediates 770 were cleaved from the resin with trifluoroacetic acid, and this was followed by ring closure with sodium hydroxide, at room temperature, to give the quinazolinone products 771 <2004JME4151>. 

Synthetic access by stepwise method to glycopeptides molecules requires flexible solution- and solid-phase combinatorial strategies. The selected... 

Solid-phase synthetic methods feature convenient purification procedures coupled with opportunities for automation. These attributes have been widely exploited to prepare libraries of small molecules via parallel and combinatorial approaches. A logical extrapolation of these efforts is the supported syntheses of larger, more complex natural products and natural product analogs. Such efforts are consistent with the pharmaceutical industry objectives behind most high-throughput syntheses since, historically, the unique properties of natural products have provided a fertile ground for... 

As the drug discovery process proceeds from early lead discovery through lead optimization and toward candidate selection, the level of purity required of each compound increases. Late-stage compounds may be tested in multiple assays, many of which may involve animal models and may be labor-intensive. Even the best solid phase combinatorial synthesis methods cannot assure that... 

Combinatorial synthesis has prompted an interest in rapid synthetic methods, particularly in the area of SPS and its application to the high-speed automated synthesis (Seneci, 2000). In solid-phase combinatorial synthesis, reagents can be used in excess without separation problems to attain complete conversion. Facile purification and automation provide further advantages. Two approaches for combinatorial synthesis of oligonu-clotides/peptides/saccharides will be considered. 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

We have been interested in a novel strategy for the efficient syntheses of natural products. During these studies, we were interested in the synthesis of a variety of their analogs utilizing combinatorial chemistry methods. - Here, we describe our recent studies of solid-phase combinatorial synthesis for a variety of naturally occurring skeletons. 

Emergence of combinatorial chemistry and parallel synthesis in early nineties and synthesis of small molecules inspired by the structural architectures of natural products in the beginning of this century called for further developments in the solid-phase synthesis protocols. Synthesis of compound libraries possessing enantiopure molecules embodying a complex framework and decorated with more than one stereocenters in a combinatorial and parallel fashion calls for highly feasible solid-phase synthesis methods." In particular, these efforts must address the stereocontrol of the reaction course in order to minimize isomer... 

Alkoxyaniline units have been used as traceless linkers for the solid-phase combinatorial synthesis of 2-arylbenzoxazoles, 2-arylbenzothioazoles, and 2-arylbenzimidazoles [40] (Scheme 18). This method has an added advantage as the products can be released from the solid support only by exposing it to an air atmosphere without any kinds of oxidants under neutral conditions. The solid support could be easily recovered and recycled after cleavage. 

However, since its implementation, solution- and solid-phase techniques have been competing with each other, and although many companies started their combinatorial chemistry program with solid-phase techniques, solution-phase combinatorial methods have taken over and now account for approximately 25% of all combinatorial efforts. 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Combinatorial chemistry (Section 27.18) A method for carrying out a large number of reactions on a small scale in the solid phase so as to generate a library of related compounds for further study, such as biological testing. 

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