Antitumor agents. 144. New gamma-lactone ring-modified arylamino etoposide analogs as inhibitors of human DNA topoisomerase II.
The trans-fused gamma-lactone ring of etoposide is readily epimerized to its cis epimer, which is biologically inactive, or is metabolized to the inactive ring-opened hydroxy acids. Modification of this gamma-lactone ring of 4 beta-(arylamino)-4'-O-demethyl-4-desoxypodophyllotoxin resulted in several compounds (15-16, 21-22, and 24) that should block this epimerization and the resulting biological deactivation. In a topoisomerase II inhibition assay, compounds 21, 22, and 24 showed comparable activity to etoposide. In a protein-linked DNA complex formation assay, compounds 21 and 22 were more active than etoposide.
Zhou
X M
XM
Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill 27599.
Lee
K J
KJ
Cheng
J
J
Wu
S S
SS
Chen
H X
HX
Guo
X
X
Cheng
Y C
YC
Lee
K H
KH
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000187:drug effects; D004987:Ethers / Q000494:pharmacology; D005047:Etoposide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004987:Ethers; D007783:Lactones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA