Synthesis and biological activity of a photoaffinity etoposide probe

The epipodophyllotoxin etoposide is a potent and widely used anticancer dru g that targets DNA topoisomerase II. The synthesis, photochemical, and biol ogical testing of a photoactivatable aromatic azido analogue of etoposide a lso containing an iodo group is described. This azido analogue should prove useful for identifying the etoposide interaction site on topoisomerase II, Irradiation of the azido analogue and an aldehyde-conntaining azido precur sor with UV light produced changes in their UV-visible spectra that were co nsistent with photoactivation. The azido analogue strongly inhibited topois omerase II and inhibited the growth of Chinese Hamster Ovary cells. Azido a nalogue-induced topoisomerase II-DNA covalent complexes were significantly increased subsequent to UV irradiation of drug-treated human leukemia K562 calls as compared to etoposide-treated cells. These results suggest that th e photoactivated form of etoposide is a more effective topoisomerase II poi son either by interacting directly with the enzyme or with DNA subsequent t o topoisnmerase II-mediated strand cleavage. (C) 2001 Elsevier Science Ltd. All rights reserved.