Biomedical Engineering Reference
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SCHEME 6.14 Chemical diversity of morpholine-based scaffolds through the reactivity of
the acetal moiety and the amino and carboxylic groups of the parent amino acid component
with a series of acid-mediated reactions. (From [34], with permission of John Wiley & Sons;
copyright C 2009 John Wiley & Sons.)
We applied the reactivity of some morpholine acetals to give access to a library
of bicyclic scaffolds containing either the ketopiperazine or the 2,5-diketopiperazine
moieties, which are considered privileged scaffolds in medicinal chemistry, owing to
the wide number of bioactive natural products and drugs containing such chemical
entities. Such a library of new chemical entities was employed in the systematic
exploration of yeast deletants to classify deletant strains as a function of bioactive
molecules. According to the synthetic strategy, skeletal diversity was accessed by
applying morpholine acetals in a one-pot multistep process giving diverse bicyclic
scaffolds as a function of the reaction methodology; the one-pot process, consisting
of a couple/cyclization sequence, enabled the generation of 2,5-diketopiperazine-
containing bicyclic compounds as a consequence of intramolecular amide bond
formation following Fmoc deprotection. The stepwise route, also consisting of a
intermediate workup step, produced a different bicyclic compound as a consequence
of the reactivity of the acetal moiety with the Fmoc-protected amino group, followed
by rearrangement [35] (Scheme 6.15).
The effects of 48 morpholine-based library members on cell growth were tested in
a phenotypic screening toward S. cerevisiae at 0.3 mM concentration on the BY4742
wild-type strain. Compounds responsible for induction variations in cell generation
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