The search
for new compounds useful for the treatment of disease continues
unabated. The emergence of resistance among many pathogens
to agents currently in clinical use is observed more and more
frequently and gives new urgency to this endeavour. The screening
of extracts derived from natural sources has provided the
lead compounds for many of the most widely prescribed drugs
in clinical use today. Although other sources of lead compounds,
in combination with new screening methodology, have made headlines
lately, there is no reason to believe that natural products
cannot continue to provide valuable leads in the future.
In collaboration
with biologists at the Cancer Reseach Center of Hawaii who
develop and run several bioassays, we are screening extracts
for several biological activities. Subsequently, we isolate
in a bio-assay guided fashion the compounds responsible for
these activities from the extracts. This is then followed
by structure elucidation, mostly by spectroscopic techniques.Compounds
of particular structural or biological interst may lead us
eventually to undertake the total synthesis or the synthesis
of analogs.
A second
area we are actively pursuing is the investigation of the
biosynthesis of several algal toxins that are found with increasing
frequency in water supplies all over the world. Two of these
toxins, the anatoxins isolated form various strains of the
blue-green alga Anabaena flos-aquae, are the subjects of ongoing
investigations. This involves the synthesis of small molecules
labeled with stable isotopes at specific positions and determination
of the fate of the label after the alga has been grown in
the presence of the labeled material.
This same
approach is taken in related, ongoing research to investigate
the mechanism by which plants elaborate alkaloids belonging
to a variety of structural types. This approach will be complemented
in the near future with work involving the isolation and characterization
of enzymes.
Selected
Publications
"Biosynthesis
of anatoxin-a in Anabaena flos-aquae and homoanatoxin-a in Oscillatoria
formosa." Hemscheidt, T.; Rapala, J.; Sivonen, K. and Skulberg,
O. J. Chem. Soc. Chem. Commun., 1995, 1361-1362
"Biosyntheis
of anatoxin-a(s). (2S,4S)-Hydroxyarginine as an intermediate."
Hemscheidt, T.; Burgoyne, D.L. and Moore, R.E. J. Chem. Soc.
Chem. Commun., 1995, 206-206
"A
classical paradigm of alkaloid biogenesis revisited. Acetonedicarboxylic
acid as an intermediate in the biosynthesis of lycopodine."
Hemscheidt, T. and Spenser, I.D. J. Am. Chem. Soc., 1996, 118,
1799-1800
"The
legume toxin mimosine is metabolised by strains of the root
nodule bacterium Rhizobium." Soedarjo, M.; Hemscheidt, T. and
Borthakur, D. Appl. and Environm. Microbiol., 1994, 64, 4268-4272
"Structure
and Biosyntheis of borophycin, a new Boeseken complex of boric
acid froma marine strain of Nostoc linckia." Hemscheidt, T.;
Puglisi, M.; Larsen, L.K.; Patterson, G.M.L.; Moore, R.E.; Rios,
J.L. and Clardy, J. J. Org. Chem. 1994, 59, 3467-3471
"Structure
and Biosynthesis of borophycin, a new Boeseken complex of boric
acid from a marine strain of Nostoc linckia." Hemscheidt, T.;
Puglisi, M.; Larsen, L.K.; Patterson, G.M.L.; Moore, R.E.; Rios,
J.L. and Clardy, J. J. Org. Chem. 1994, 59, 3467-3471
