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Science 22 May 1992:
Vol. 256. no. 5060, pp. 1172 - 1178
DOI: 10.1126/science.256.5060.1172
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Articles

Designed Enediynes: A New Class of DNA-Cleaving Molecules with Potent and Selective Anticancer Activity

K. C. Nicolaou 1, W.-M. Dai 2, S.-C. Tsay 2, V. A. Estevez 1, and W. Wrasidlo 2

1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemistry, University of California, San Diego, La Jolla, CA 92093
2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037

The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are mainfested in potent anticancer activity with remarkable selectivities. Their mechanism of action reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.


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