Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 115

bizelesin was selected by the National Cancer Institute and the Upjohn Com-
pany for development in clinical trials in the USA [92].
Epothilone was first discovered by Höfle and Reichenbach at the GBF in
Germany in 1987 within a screening for antifungal agents from the cultures ofthe
myxobacterium Sorangium cellulosum [94].In 1995,Merck & Co.reported on its
interaction with the microtubuli ofcells in a paclitaxel like manner [93].Although
epothilone does not reveal any structure similarity to paclitaxel [95] it turned out
to be superior to paclitaxel referring to potency in cell culture assays of multi-
drug-resistant tumor cell lines.The microbial metabolite epothilone is accessible
in almost unlimited quantities by fermentation. Furthermore, it overcomes
solubility problems in water that substantially reduce paclitaxel compliance.Total
synthesis towards epothilone and analogs as well as modification reactions
[96-98] starting from epothilone aim at epothilone derivatives with improved
performance.In 1997,Bristol-Myers Squibb has signed a contract with the GBF for
extended investigation towards an epothilone based novel anticancer drug sup-
plementing the therapeutic range ofBristol-Myers Squibb's pharmaceutical Taxol.
A natural products screening for inhibitors of the squalene synthase, a late
enzymatic step in the biosynthetic pathway leading to cholesterol,gave rise to
the parallel discovery of novel highly oxygenated types of fungal metabolites
called zaragozic acids (Merck [99]), and squalestatins (Glaxo [100], and Mit-
subishi Kasei [101]).The compounds exhibit IC 50 values in the nanomolar range
(rat enzyme). Although cholesterol biosynthesis is substantially reduced in
various animal models by oral application ofzaragozic acids/squalestatins their
toxicity profile comprising accumulation of farnesyl-derived dicarboxylic acids
presumably will prevent medicinal use as antihypercholesterolemic drugs.
However, due to their structural similarity with farnesyl pyrophosphate the
zaragozic acids/squalestatins also interact with farnesyl transferase,a promising
target for new anticancer therapeutics [102].
3.2
Clinical Candidates from Plants
The impact of Traditional Chinese Medicine on modern western drugs is demon-
strated not only by commercialized therapeutic agents such as camptothecin or
artemisinin but also by clinical candidates like huperzine A, an acetylcholin-
esterase inhibitor to treat Alzheimer's disease [103].Huperzine A can be isolated
from both, Huperzia serrata ,and H.selago [104,105].Because huperzine A is pro-
duced only at very low levels a synthetic approach has been developed in order to
provide sufficient quantities for preclinical toxicology studies and clinical trials.
3.3
Clinical Candidates from Marine Environment
Recent trends in drug discovery from natural sources emphasize investigation
of the marine environment yielding numerous,often highly complex chemical
structures [106-108]. So far, in most cases in vitro cultivation techniques
towards the supply with sufficient quantities for exhaustive biological activity