New anthracenedione derivatives with improved biological activity by virtue of stable drug-DNA adduct formation.
Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the "linker" region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with ∼100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug-DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.
Mansour
Oula C
OC
Department of Biochemistry, La Trobe University, Victoria 3086, Australia.
Evison
Benny J
BJ
Sleebs
Brad E
BE
Watson
Keith G
KG
Nudelman
Abraham
A
Rephaeli
Ada
A
Buck
Damian P
DP
Collins
J Grant
JG
Bilardi
Rebecca A
RA
Phillips
Don R
DR
Cutts
Suzanne M
SM
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D005557:Formaldehyde / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008942:Mitoxantrone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D000880:Anthraquinones; D000970:Antineoplastic Agents; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D007546:Isoquinolines; D011355:Prodrugs; D005557:Formaldehyde; D008942:Mitoxantrone; D012321:DNA-Directed RNA Polymerases; C086548:pixantrone