Designed enediynes: a new class of DNA-cleaving molecules with potent and selective anticancer activity.
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 manifested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly 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.
Nicolaou
K C
KC
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037.
Dai
W M
WM
Tsay
S C
SC
Estevez
V A
VA
Wrasidlo
W
W
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents