DNA but not topoisomerases is a target for a cytotoxic benzo[5,6]cyclohepta[b]indol-6-one derivative.
The interaction of a newly designed benzocycloheptaindol-6-one derivative with DNA has been investigated by complementary spectroscopic techniques including absorption, circular and linear dichroism. Footprinting measurements were performed to delineate the sequence-selectivity of the drug-DNA interaction and a plasmid relaxation assay was used to study the effects of the drug on human DNA topoisomerases I and II. The results clearly indicated that the test compound behaves as a typical DNA intercalating agent but does not stimulate DNA cleavage by topoisomerases. At the cellular level, the cytometry measurements showed that the drug provoked a marked accumulation of HL60 human leukemia cells in the G2/M phase of the cell cycle. DNA is thus identified as a valid target for this new series of drugs particularly toxic to human (HL60) and murine (P388) leukemia cells.
Benoit
J
J
Institut de Chimie Organique et Analytiqué, associe au CNRS, Université d'Orléans, France.
Routier
S
S
Mérour
J Y
JY
Colson
P
P
Houssier
C
C
Bailly
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle; D003508:Cycloheptanes / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008968:Molecular Conformation
D000970:Antineoplastic Agents; D003508:Cycloheptanes; D004273:DNA, Neoplasm; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II