Combinatorial scaffolds

Fig. 3 a-Isocyanoamides as the starting materials for a plethora of combinatorial scaffolds. The isocyanide borne moiety in the scaffolds is marked blue... 

Wu, X., Ding, Q., Schultz, P. G. (2002) A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J Am Chem Soc 124, 1594-1596. 

T. R. Webb, Application of a novel design paradigm to generate general nonpeptide combinatorial scaffolds mimicking beta turns synthesis of ligands for somatostatin receptors, Bioorg. and Med. Chem. 2003, 11, 5059-5068. 

Fast binary filtering methods can also be used for scaffold ranking, i.e., the prioritization of combinatorial scaffolds based on predicted properties. Privileged scaffolds were selected to demonstrate this idea [82], Piperazines SI, benzodiazepines S2, and spiroindolines S3 have been described as GPCR-privileged scaffolds [83], Scaffold S4 represents a SPIKET motif for tubulin binding which is effective for inhibiting cellular proliferation [84], Dysidiolide-derived compounds... 

Steele, J.A., MccuUen, S.D., CaUanan, A., Autefage, H., Accardi, M.A., Dini, D., Stevens, M.M., 2014. Combinatorial scaffold morphologies for zonal articular cartilage engineering. Acta Biomater. 10, 2065—2075. 

Figure 8 Combinatorial scaffolds used by Sadowski, Wagener, and Gasteiger (a) xanthene (b) cubane (c) adamantane...

Eucaryotes have many more genes and a broader range of specific transcription factors than procaryotes and gene expression is regulated by using sets of these factors in a combinatorial way. Eucaryotes have found several different solutions to the problem of producing a three-dimensional scaffold that allows a protein to interact specifically with DNA. In the next chapter we shall discuss some of the solutions that have no counterpart in procaryotes. However, the procaryotic helix-turn-helix solution to this problem (see Chapter 8) is also exploited in eucaryotes, in homeodomain proteins and some other families of transcription factors. 

EMPl, selected by phage display from random peptide libraries, demonstrates that a dimer of a 20-residue peptide can mimic the function of a monomeric 166-residue protein. In contrast to the minimized Z domain, this selected peptide shares neither the sequence nor the structure of the natural hormone. Thus, there can be a number of ways to solve a molecular recognition problem, and combinatorial methods such as phage display allow us to sort through a multitude of structural scaffolds to discover novel solutions. 

Recently it has been shown that the microwave-assisted decoration of the 2(lff)-pyrazinone scaffold can allow an easy introduction of different substituents at the C-3 and even to the less reactive C-5 position [29]. Taking full advantage of combinatorial principles, some of these pathways were transferred to microwave-enhanced solid-phase chemistry, opening the way for the generation of many biologically interesting structures [108]. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

Krier M, de Araujo-Junior JX, Schmitt M, Duranton J, Justiano-Basaran H, Lugnier C, Bourguignon JJ, Rognan D. Design of small-sized libraries by combinatorial assembly of linkers and functional groups to a given scaffold application to the structure-based optimization of a phosphodiesterase 4 inhibitor. J Med Chem 2005 48 3816-22. 

The concept of minimum AE and maximum Emw is illustrated with the generalized sequence shown in Scheme 4.7 under stoichiometric conditions with complete recovery of reaction solvents, catalysts, and post-reaction materials. Markush structures are used to show both variable R groups and necessarily invariant atoms. This analysis is useful in studying combinatorial hbraries where a constant scaffold structure is selected and then is decorated with, in principle, an unlimited number of possible R groups. 

Lee, M.L. Schneider, G. (2001) Scaffold Architecture and Pharmacophoric Properties of Natural Products and Trade Drugs Application in the Design of Natural Product-Based Combinatorial Libraries. Journal of Combinatorial Chemistry, 3, 284-289. 

Fig. 21 Synthetic scheme of benzimidazolium scaffold-based combinatorial library and their general structures and photophysical properties of the representative examples. All the photophysical properties were measured in methanol...

Rosania GR, Lee JW, Ding L, Yoon HS, Chang YT (2003) Combinatorial approach to organelle-targeted fluorescent library based on the styryl scaffold. J Am Chem Soc 125 1130-1131... 

All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often one pot , ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

In the absence of any information about the structure of a target, combinatorial synthesis can be used to explore a set of diverse scaffolds that direct potential binding interactions to different angles and distances from each other. The structure-activity relationship that emerges from... 

Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

The SHAPES Linking Library was designed to facilitate the use of combinatorial chemistry to follow up screening hits [11]. This library consists primarily of commercially available compounds containing two drug-like scaffolds connected by a linkage that is synthetically accessible. To construct this library, a database of commercially available compounds was filtered to select for drug-likeness and the presence of the desired molecular... 

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