Deconvolution recursive

Bodenhausen ° developed a pattern-recognition programme (MARCO POLO) in order to extract coupling pathways in COSY spectra. He subsequently described a recursive deconvolution technique for the measurement of couplings, but this seems to offer more benefits to the measurement of scalar couplings in two-dimensional spectra than in one-dimensional spectra. 

In recursive deconvolution, after the addition of a new building block, a sample of that batch of resin is set aside and cataloged. Furthermore, after the final step, the resin is not repooled, so the last step for all the library members remains known. The cataloged resins and knowledge of the last step facilitate deconvolution.21... 

Recursive deconvolution is perhaps best explained through a simple eight compound library prepared by three steps, addition of A or B, then / or 2, and finally a or b (Scheme 9.12). In total, such a library has four resin samples. The resin samples are cataloged from intermediate steps—two samples each from the A/B step and the 112 step. Assume the library gives one hit in a screen. The screener of the library knows only the last step leading to the hit. In this case, the hit is Alb. The screener would know only the last step that produced hit, so the hit would be b, with being the unknown building blocks from steps one and two.21... 

A 27-member library was prepared by split synthesis in three steps. Each step involved three different building blocks A, B, C 1, 2, 3 and a, b, c. The library afforded one hit. In a recursive deconvolution of the library, how many compounds would need to be made and tested to determine the identity of the hit For a hypothetical three-step library of steps involving x, y, and z building blocks, how many compound syntheses would be required for recursive deconvolution How many compounds would be required to deconvolve a four-step library of m, n, o, and p building blocks ... 

In a related strategy termed recursive deconvolution [16], samples of all sublibraries at each stage are retained. With this approach it is not necessary to repeat the entire synthesis at each stage of the deconvolution. One simply adds the previously determined preferred synthons to the reserved sublibraries. 

Erb E, Janda KD, Brenner S, Recursive deconvolution of combinatorial chemical libraries, Proc. Natl. Acad. Sci. USA, 91 11422-11426, 1994. 

These techniques can be broadly split into two groups, the first of which can be represented by pooling methods, where deconvolution is obtained via various chemical steps, run in parallel or after the library synthesis. Pooling methods normally require multiple synthesis of many library members, including inactive individuals, in different pool formats. They are not single bead methods, so they are independent from analytical methods for structure determination. This group includes iterative deconvolution, recursive deconvolution, subtractive deconvolution, positional scanning and mutational... 

Iterative deconvolution Recursive deconvolution Subtractive deconvolution Positional scanning/indexing Mutational surf other methods... 

The second group can be represented by single bead methods, and relies on either bioanalytical methods to select the active compounds or on-bead screening to determine the beads carrying active compounds. It is limited to solid-phase chemistry and does not require chemical steps after library synthesis but does require sophisticated analytical methods to determine the structure of the active compounds. A recent hybrid deconvolution-single beaddecoding method named DRED (dual recursive deconvolution) requires both deconvolutive techniques and sophisticated analytical capacities. 

Whilst the same researchers are using new scaffolds and non-peptide chemistries to generate other libraries [31], Kung et al. [32] used this deconvolutive technique on a SPSAF (solution-phase simultaneous Addition of Functionalities) generated library, and Davis et al. [33] reported the recursive deconvolution of a peptidomimetic library of potential artificial enzymes. A future application could be in the popular field of libraries from multicomponent reactions [34], either in solution or in solid phase, which are difficult to deconvolute with classical methods due to the mixtures of components reacting at the same time. 

Figure 3. Liquid phase combinatorial synthesis (LPCS) and recursive deconvolution.

In one serial deconvolution protocol, called the synthetic combinatorial library [6,7], groups of related mixtures, each having one or two defined positions, are created and screened in solution, as depicted in Fig. 2. In this example, the BXX mixture is found to have the highest activity after the first iteration, where X is of indeterminate composition. From the BXX mixture, additional sublibraries are created and screened, thereby defining the second position, BCX. This process is repeated until each of the positions in the compound are defined and the most promising candidate, BCA, is identified. In a related approach known as recursive deconvolution, the library is prepared in the same way, except that a portion of each resin is retained prior to each divide-and-combine step [8]. This is advantageous in that intermediate sublibraries do not have to be resynthesized after each screening. 

E Erb, KD Janda, S Brenner. Recursive deconvolution of combinatorial chemical Libraries. Proc Nad Acad Sci USA 91 11422-11426,1994. 

A number of modifications have been reported in order to address these complications. Janda has noted that during the first split-pool procedure, resin can be saved at each cycle immediately prior to resin pooling.This resin can later be used as an intermediate in the iterative resynthesis and deconvolution procedure (recursive deconvolution) [109]. This results in considerable savings in time and effort. 

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