Biomedical Engineering Reference
In-Depth Information
the active principles and to elucidate their structures.However,if one considers
the diversity of chemical structures found in nature with the narrow spectrum
of structural variation of even the largest combinatorial library it can be ex-
pected that natural products will become important again [4].Mainly actinomy-
cetes, fungi and higher plants have been shown to biosynthesize secondary
metabolites of obviously unlimited structural diversity that can further be
enlarged by structure modification applying strategies of combinatorial chem-
istry. Probably, a variety of novel concepts in natural products research is re-
quired to attract interest in incorporating natural sources into the HTS process.
For instance,a “Natural Products Pool”comprising only pure and structural-
ly defined compounds has currently been established in the 96-well microplate
format in Germany.The project aims at providing an infrastructure that impro-
ves the availability of natural products, their derivatives and analogs for in-
dustrial screening assays restricted to the minimum amount of test sample
needed.Only a minority of the natural products known so far have been biolo-
gically characterized in detail. Therefore, any novel target-directed screening
assay may result in identification of a new lead structure even from sample
collections comprising already described compounds.
Recent strategies in combinatorial chemistry aim at synthesizing single com-
pounds or definite mixtures ofonly a few components.This trend was accelerat-
ed when it became evident that complex mixtures derived from “split and com-
bine”strategies often failed in HTS bioassays.Limitations are substantial with
respect to cell-based screening assays. These facts indicate that results from
testing traditional extracts from natural sources such as plants or microbial
cultures have to be questioned.Therefore,generating high quality test samples
of less complexity and accelerated reproducibility is favorable in order to com-
pete successfully with combinatorial chemistry.
Today, selected targets of interest are transferred to the HTS aiming at dis-
covering a “hit”,and subsequently a lead structure within one to two months.
After that time, the target concerned is replaced by a new one. Thus, rapid
characterization and structure elucidation of the active principles of interest
from natural sources are critical with reference to competition with synthetic
libraries of pure and structurally defined compounds. Elaboration of LC-MS
and LC-NMR techniques to accelerate structure elucidation of bioactive prin-
ciples from natural sources is currently underway.Combination ofthese techni-
ques with databases comprising a maximum of known natural compounds will
probably contribute substantially to more interest in natural products for appli-
cation in drug discovery.
Indications that today only a small percentage of living organisms have been
described implies that there is an enormous reservoir of natural compounds of
great structural diversity which are still to be discovered. The United Nations
Convention on Biological Diversity adopted in Rio de Janeiro in 1992 sets the
basic principles of access to and exploitation of global biological sources in the
future.The Convention introduces national ownership of biological resources.
As a result, various pharmaceutical companies fear that this will cut off the
flow of genetic resource materials for industrial drug discovery. However, the
Convention has not yet been ratified by the USA.
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