We have developed a two steps strategy for the parallel synthesis of highly diversified quinolin-ones. In the first step we have combined and improved different synthetic methods for generating quinolin-4-ones bearing four different substitutions at specific positions using round bottomed flasks. The synthesis was assessed for a large number of substituted quinolin-4-ones. In the second step, the improved method was adapted to a parallel array synthesis using a 12 positions carrousel as demonstrated for the synthesis of 42-variable quinolin-4-ones. The first combinatorial library set 14(a-x) was obtained with a chemical purity of more than 95% without purification, the second library set 15(a-r), which included two synthetic steps, needed combinatorial purification using an innovative parallel purifier. The proposed approach contributes to a more extensive diversification of molecular scaffolds in general and provides access to highly substituted quinolinones in particular.
A practical and relatively simple method to identify molecularly imprinted polymers capable of binding proteins via the molecular tagging (epitope-like) approach has been developed. In our two-step method, we first challenge a previously obtained anti-tag molecularly imprinted polymer with a small molecule including the said tag of choice (a biotin derivative as shown here or other) connected to a linker bound to a second biotin moiety. An avidin molecule partially decorated with fluorescent labels is then allowed to bind the available biotin derivative associated with the polymer matrix. At the end of this simple process, and after washing off all the low-affinity binding molecules from the polymer matrix, only suitable molecularly imprinted polymers binding avidin through its previously acquired small molecule tag (or epitope-like probe, in a general case) will remain fluorescent. For confirmation, we tested the selective performance of the anti-biotin molecularly imprinted polymer binding it to biotinylated alkaline phosphatase. Residual chemical activity of the enzyme on the molecularly imprinted polymer solid support was observed. In all cases, the corresponding nonimprinted polymer controls were inactive.
A fast synthesis of ring-A disubstituted Fmoc and Boc protected L-tryptophan analogs was achieved starting from the appropriate 2,4-or 2,3-disubstituted phenylhydrazines and optically active N,N-diprotected L-glutamic acid g-aldehydes, utilizing a Fischer-indole synthesis as a key step. Unlike most of the previously reported methods, that required the multistep stereoselective generation of a chiral carbon, this fast methodology is useful for generating optically active ring-A disubstituted protected tryptophans starting from a simple and common chiral precursor. These building blocks have a wide application scope in peptide and combinatorial chemistry fields.
A fast synthesis of ring-A disubstituted Fmoc and Boc protected L-tryptophan analogs was achieved starting from the appropriate 2,4-or 2,3-disubstituted phenylhydrazines and optically active N,N-diprotected L-glutamic acid g-aldehydes, utilizing a Fischer-indole synthesis as a key step. Unlike most of the previously reported methods, that required the multistep stereoselective generation of a chiral carbon, this fast methodology is useful for generating optically active ring-A disubstituted protected tryptophans starting from a simple and common chiral precursor. These building blocks have a wide application scope in peptide and combinatorial chemistry fields.
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