Biomedical Engineering Reference
In-Depth Information
Fig. 10.
Structure activity relationships of epothilone provided by combinatorial natural pro-
duct chemistry
acid with various building blocks to achieve test compounds with molecular
masses of more than 600 Dalton.
A new approach to obtain increased diversity in the search for new lead com-
pounds called kombiNATURik has been co-developed by the German compa-
nies AnalytiCon and Jerini Bio Tools.The kombiNATURik program starts from
natural compounds which are further diversified by solid-support chemistry
introducing e.g. peptide or carbohydrate moieties. KombiNATURik libraries
generally comprise several hundreds to thousands of single molecules derived
from multi-parallel synthesis.
Future success in combinatorial chemistry will substantially depend on both,
the structural diversity,and biological activity ofcompounds submitted to HTS.
Up to now,structural diversity ofcombinatorial libraries is limited because their
design is guided more by the chemical reactions currently adaptable to com-
binatorial chemistry, than by biological requirements. It turned out that low-
molecular mass compounds of up to 400 to 500 Dalton if they are synthesized
within conventional combinatorial chemistry attempts seem to fail affecting
disease related protein/protein or protein/DNA interactions sufficiently. Com-
binatorial chemistry starting from natural compounds as building blocks or
templates of approximately 400 to 500 Dalton resulting in molecules of 700 to
800 Dalton can fill this gap.These nature-derived molecules promise improved
properties towards the inhibition ofbiomacromolecular interactions which play
important roles e.g. in the regulation of cell growth and differentiation pro-
cesses.
Today, it is obvious that in drug discovery combinatorial chemistry cannot
displace natural product research.However,natural product chemistry can take
advantage of combinatorial strategies.In our opinion,the discovery and devel-
opment of innovative therapeutic agents will substantially benefit from the
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