Chemistry Reference
In-Depth Information
computer modeling for the design of enzyme inhibitors can be found in Chapter
2. Some examples of inhibitors of carbohydrate biosynthesis that are showing
promise as therapeutic agents are highlighted in Figure 28.2. Many of these are
derived from natural products, as discussed in Info Box 2 .
In another line of cancer therapy research, efforts have been made to inhibit the
interactions between the cancer-associated carbohydrates and the tissue receptors
(lectins) (for examples, please see Chapter 25). This has proved particularly inter-
esting for aborting metastatic processes, as interactions between tumor- associated
carbohydrates and receptors on endothelial cells are widely implicated as being
essential for the metastatic spread. Thus, considerable effort has been committed
to synthesizing mimetics of tumor-associated carbohydrate antigens with the aim
of producing derivatives that bind more strongly to the lectin receptors than the
natural carbohydrate ligands [6, 7]. Indeed, recent clinical trials have reported that
administration of sialyl - Lewis
x
( Le
x
) (Figure 28.3) mimetics offers such a potential.
These mimetics can potentially block selectin-carbohydrate binding by occupying
the selectin-binding sites (for the X-ray structure of sialyl- Le
x
and P - selectin, please
see Figure 16.1h, for further information on selectins, please see Chapter 27).
Although many anticancer therapies based on carbohydrates are still at the
research and development stage, it is likely they will ultimately offer many advan-
tages over conventional therapies. The potential of carbohydrate- based vaccines
for treating cancer has been greatly improved by conjugating carbohydrates, which
themselves display limited immunogenicity, with immunogenic proteins, or by
presenting them as dendrimers (see Chapter 4 for structural aspects). Improved
antibody-inducing capabilities have also been obtained by adding separate adju-
vants to their formulations.
Info Box 2
Many leads for drug development are obtained from natural systems. Nature
is able to prepare complex compounds through the use of enzymes. These can
be isolated and their biological properties assessed through biological screens.
Compounds that show the desired activity can then be further developed and
new derivatives prepared as part of the drug development process. Imino
sugars are examples of naturally occurring molecules that have been further
developed by scientists to produce useful drugs. These sugar analogs are found
in plants and microbes, and may inhibit enzymes associated with a range of
diseases. The fi rst natural imino sugar, nojirimycin, was discovered in Japan
in 1966 from the broth containing a
Streptomyces
species. Castanospermine is
another effective enzyme inhibitor that can be isolated from the Australian tree
astanospermum. Research into modifying nojirimycin, castanospermine and
related analogs has resulted in new inhibitors with improved selectivities, activi-
ties and solubilities. These analogs have been marketed for the treatment of
many diseases including diabetes (miglitol was the fi rst imino sugar drug to
reach the market) and Gaucher's disease (see Chapter 10.14).
