Synthesis and biological activity of a photoaffinity etoposide probe.
The epipodophyllotoxin etoposide is a potent and widely used anticancer drug that targets DNA topoisomerase II. The synthesis, photochemical, and biological testing of a photoactivatable aromatic azido analogue of etoposide also 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-containing azido precursor with UV light produced changes in their UV--visible spectra that were consistent with photoactivation. The azido analogue strongly inhibited topoisomerase II and inhibited the growth of Chinese Hamster Ovary cells. Azido analogue-induced topoisomerase II--DNA covalent complexes were significantly increased subsequent to UV irradiation of drug-treated human leukemia K562 cells as compared to etoposide-treated cells. These results suggest that the photoactivated form of etoposide is a more effective topoisomerase II poison either by interacting directly with the enzyme or with DNA subsequent to topoisomerase II-mediated strand cleavage.
Hasinoff
B B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada. b_hasinoff@umanitob.ca
Chee
G L
GL
Day
B W
BW
Avor
K S
KS
Barnabé
N
N
Thampatty
P
P
Yalowich
J C
JC
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005047:Etoposide / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000494:pharmacology*; D010777:Photochemistry; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019920:Photoaffinity Labels; D059005:Topoisomerase II Inhibitors; D005047:Etoposide