Positional scanning, active compound identified

Because of their ease of synthesis and their structural similarity to peptides, many laboratories have used peptoids as the basis for combinatorial drug discovery. Peptoids were among the first non-natural compounds used to establish the basic principles and practical methods of combinatorial discovery [17]. Typically, diverse libraries of relatively short peptoids (< 10 residues) are synthesized by the mix-and-split method and then screened for biological activity. Individual active compounds can then be identified by iterative re-synthesis, sequencing of compounds on individual beads, or indirect deduction by the preparation of positional scanning libraries. 

A process called deconvolution is commonly employed to determine biological activity.The final library pools are not combined but are tested as either on-bead or detached compound mixtures. The most active pool defines which synthon is preferred in the last step. The synthesis is repeated to the penultimate set of pools and these are then allowed to react with the best last step synthon. Alternatively, pools of conserved resin from the penultimate step held back during the original synthesis may be used. The most active pool found on retesting defines the best last two synthons. This process is repeated until the most active member is identified. A somewhat similar method termed position scanning also has found successful application, especially in the analysis of peptides. ... 

However, if in one position there is no clear preference for a definitive substituent, all combinations of the preferred substituent must be synthesized in order to find the most active compound. Although active compounds are identified without iterative synthesis using positional scanning, in comparison with iterative deconvolution there is an increased likelihood that the most potent compound(s) will not be identified [110,111]. 

Extensive studies of the use of mixtures carried out by this laboratory and others have enabled the rapid, cost-effective identification of extremely active, highly specific individual compounds as reviewed in this chapter. There appears to be widespread skepticism that mixtures in combination with the positional scanning approach are effective in identifying active heterocycles, although they are widely accepted as methods for identifying peptides. However, these methods clearly are extremely effective and broadly applicable, as has been shown in this chapter and in many other studies. There is also nothing inherently unique about peptides or other oligomers that permits their successful use in these formats as compared with heterocycles. 

There are several ways to deconvolute or identify the individual active compounds in an active mixture. These include iterative resynthesis and the synthesis of overlapping mixtures, such as the positional scanning method of Houghten et al." In iterative resynthesis, the most active pools are resynthesized as several smaller subpools with a variable position resolved. This process is repeated until every position has been resolved and individual active compounds have been made. In Houghten s method, the complete library is... 

However, TRIR has also been applied to more classical coordination compounds. Ford and co-workers have used a combination of ns-TRIR and time-resolved UV/vis spectroscopy to investigate the mechanism of hydrocarbon C—H bond activation with the rhodium complex, trans-RhCl(CO)(PR3)2 (R = Ph, />-tolyl, or Me). Upon photoexdtation, each of these species was found to undergo CO dissociation to form the transient solvated complex, tra 5-RhCl(Sol)(PR3)2 (Sol = solvent). The solvated complexes reacted with added CO to regenerate the parent complex, and also underwent competitive unimolecular C H activation to form the Rh products of hydrocarbon oxidative addition. These were identified from the step scan FTIR spectra, which showed a positive shift in /(CO) relative to the parent complex, which is consistent with oxidation of the metal center. 

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