Synthesis and anticancer activities of 6-amino amonafide derivatives.
Amonafide is a DNA intercalator and topoisomerase II inhibitor in clinical development for the treatment of neoplastic diseases. Amonafide contains a free arylamine, which causes it to be metabolized in humans by N-acetyl transferase-2 (NAT2) into a toxic form. To eliminate the NAT2 acetylation of amonafide while retaining the anticancer properties, we have synthesized nine derivatives that are structurally similar to amonafide that should not be acetylated. Eight derivatives have arylamines at the 6-position (vs. 5-position of amonafide) and one derivative completely lacks the arylamine. The derivative with a free amine in the 6-position and one with a substituted amine in the 6-position are not acetylated, whereas amonafide is extensively acetylated as determined by an NAT2 assay. The biological activities of these compounds were evaluated to determine whether they behaved similarly to amonafide in purified systems and in vitro. We found that three compounds had similar cancer cell-selective growth inhibition to amonafide, while retaining similar subcellular localization, DNA intercalation and topoisomerase II inhibition activities. In addition, these compounds were able to eliminate a marker of metastatic potential, the perinucleolar compartment. These three compounds (named numonafides) might thus allow for better patient management than those treated with amonafide; hence, they should be developed further as potential clinical replacements for amonafide or as novel anticancer drugs.
Norton
John T
JT
Department of Cell and Molecular Biology, The Mary Beth Donnelley Clinical Pharmacology Core Facility, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Witschi
Mark A
MA
Luong
Lynn
L
Kawamura
Akane
A
Ghosh
Supurna
S
Stack
M Sharon
MS
Sim
Edith
E
Avram
Michael J
MJ
Appella
Daniel H
DH
Huang
Sui
S
D000107:Acetylation; D000225:Adenine; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004249:DNA Damage; D006801:Humans; D007094:Imides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D053644:Naphthalimides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D063065:Organophosphonates; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D007094:Imides; D007364:Intercalating Agents; D007546:Isoquinolines; D053644:Naphthalimides; D063065:Organophosphonates; D059004:Topoisomerase I Inhibitors; C037020:amonafide; D004247:DNA; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D000225:Adenine