Chemical genetics compound libraries

It is critical to this chemical genetic approach to have a library of compounds that have a high probability of being relatively selective otherwise, the ability to interpret the results becomes at least as complex as deciphering highly poly-genetic phenotypes. To address this, diversity-oriented synthesis has been proposed to provide arrays of complex small molecules that are easily synthesized. The natural-product basis for many of the molecules and their complexity are believed to contribute to their cellular potency and selectivity (6). This chemical genetic approach has been applied to identify novel inhibitors of alpha-tubulin and histone deactylation (7). 

Recently, new comprehensive approaches have been developed that use compound libraries for screens in whole living cells using specific phenotype readouts. Some of the applications of this type of approach have been called chemical genetics or chemogenomics [9-27]. In many instances it is probably more accurate to call... 

Collections of compounds, so-called libraries, are the absolute starting point for any chemical genetics study. These library compounds can be either natural products or synthetic compounds with various designs. 

Fig. 6-20 Forward chemical-genetic screen for inhibitors of protein deacetylation (data from Ref. 80). (a) Overview of cell-based screens of the 1,3-dioxane-based, diversity-oriented synthesis-derived library using antibodies to measure tubulin and histone acetylation, (b) Relative position of selected active compounds in a three-dimensional principal component model computed from five cell-based assay descriptors. AcTubulin-selective (red),...

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

The final example of our chemical genetic approach to dissect herbicide action involves auxin biology. A subset of our bioactive compound library that exhibited auxinic herbicidal symptoms was tested for inhibition of root growth of Arabidopsis seedlings. The most potent of these compounds was a novel picolinate auxin DAS534. Previous mutational studies with 2,4-D have elucidated an auxin signal-... 

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