Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 113

camptothecin topotecan irinotecan

Fig. 5. Camptothecin-derived drugs topotecan,and irinotecan

and total synthesis in 1983 [71].Artemisinin is actually applied in Asian coun-
tries in cases ofmalaria caused by strains of Plasmodium falsiparum resistant to
therapeutics of the chloroquine and mefloquine type [72,73].Artemisinin ex-
hibits only moderate acute toxicity but considerable side effects. Thus, for
approval in European countries artemether which is a semi-synthetic derivative
of artemisinin indicating improved tolerance has been developed [74].

3
Clinical Candidates Derived from Natural Sources

3.1
Clinical Candidates from Microorganisms

Due to failures in cancer therapy,numerous compounds derived from various
natural sources are under preclinical or clinical trials in order to study their
therapeutic value.One example is the extremely toxic enediynes isolated from
actinomycetes strains.Featuring a cis -configurated double bond adjacent to two
triple bonds within a macrocyclic ring system as a part of a highly complex
molecule, the enediyne structure was first described for neocarzinostatin in
1965 [75]. Other members of the enediyne antibiotic class, the esperamicins
[76],the calicheamicins [77],both featuring a unique allylic trisulfide attached
to a bridgehead carbon atom, and dynemicin A [78] were discovered in the
mid- to late 1980s.All these compounds appear to share two modes of action
which comprise DNA intercalation to the minor groove,and second a thiol or
NADPH triggered reaction generating radicals that cleave DNA [79].A Bergman
reaction represents the key step that leads to the formation of a highly reactive
diradical being responsible for DNA strand scission by abstracting hydrogen
atoms at the C-1

position of the DNA sugar-phosphate residues
within the minor groove.In vitro studies implicate sequence selectivity for DNA
strand scission ranging from base preferences of the esperamicins at thymidine
to cytidine for the calicheamicins, and guanine for dynemicin A, respectively.

¢ , C-4 ¢ or C-5 ¢