Synthesis, DNA-binding and cytotoxic properties of a bis(netropsin)-anthracenedione conjugate.
A combilexin molecule containing two netropsin moieties attached to the aminoalkyl side chains of mitoxantrone has been synthesized and evaluated for cytotoxic activity towards murine L1210 leukaemia and human MCF7 carcinoma cells in vitro. It is marginally less cytotoxic than mitoxantrone but much more growth-inhibitory than netropsin. Various spectroscopic and biochemical techniques have been employed to characterize the interaction of the drug, NetMitox, with DNA. Circular dichroism (CD) and electric linear dichroism (ELD) data indicate that binding of the netropsin moiety or moieties within the minor groove of the double helix impedes the intercalation of the adjacent anthracenedione ring. ELD and footprinting experiments reveal a certain amount of mutual interference between the two functionalities of the conjugate molecule but the selective recognition of AT-rich sequences by netropsin largely dominates the recognition pattern. The lack of interaction with GC-rich sequences is attributable to steric hindrance occasioned by the 2-amino group of guanine which impedes access of the netropsin moiety into the minor groove, as is evident by the good binding of the hybrid to poly(dI-dC) x poly(dI-dC) as well as by the redistribution of its binding sites on DNA molecules substituted with inosine and/or 2,6-diaminopurine. The difficulty of the anthracenedione system in intercalating correlates with the lack of effect of the drug on cleavable complex formation with topoisomerase II as well as its diminished cytotoxicity compared to mitoxantrone. However, the finding that the drug retains significant toxicity towards leukaemia cells may suggest that DNA is perhaps not the unique molecular target.
Boitte
N
N
Institut de Chimie Pharmaceutique, Lille, France.
Pommery
N
N
Colson
P
P
Houssier
C
C
Waring
M J
MJ
Hénichart
J P
JP
Bailly
C
C
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D018983:DNA Footprinting; D004273:DNA, Neoplasm / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives*; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013057:Spectrum Analysis; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014783:Viscosity
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; C108370:bis(netropsin)-anthracenedione conjugate; D009429:Netropsin; D008942:Mitoxantrone