Biomedical Engineering Reference
In-Depth Information
However,as there is no free DNA in the cell,and the real target for DNA-inter-
active agents is the chromatin,it is not clear whether in vitro studies can con-
tribute to understanding of cellular DNA sequence selectivity.Various synthetic
approaches and mechanistic studies assisted by computer aided molecular
design (CAMD) have been described aiming at an optimization of the pharma-
cological properties of the enediyne antibiotics [80]. It remains to be seen
whether enediynes,either natural or designed,will become a useful supplement
to the arsenal for the treatment of cancer.
A further example emphasizes the relevance of microbial metabolites in the
development of novel antitumor drugs.CC 1065 was discovered at the Upjohn
Company as an extremely cytotoxic metabolite from the culture broths of
Strep-
tomyces spec.
[81,82].Hepatotoxic properties with LD
50
of 9 mg/kg (mice i.v.)
prevent therapeutic use of the natural product.Investigation on the molecular
mechanism ofaction together with chemical modification ofthe basic structure
[83-86] resulted in the bifunctional synthetic analog bizelesin [87] that bears an
urea moiety linked symmetrically to two DNA binding and alkylating groups.
Bizelesin is unique among the analogs with bifunctional alkylating capability
due to two chloromethyl moieties which are converted to the cyclopropyl al-
kylating species that interacting DNA by producing interstrand cross-links
[88-91].As bizelesin did not lead to delayed deaths when applied in therapeutic
doses to mice, and due to its breadth of antitumor activity, potency, unique
mechanism of action,and lack of cross-resistance with other alkylating agents,
CC 1065
epothilone B
bizelesin
esperamicins
Fig. 6.
Microbial metabolites esperamicin,CC 1065,and epothilone comprising potential anti-
cancer activity.Starting from CC 1065 as a lead structure bizelesin was synthesized.
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