Bisimidazoacridones and related compounds: new antineoplastic agents with high selectivity against colon tumors.
A new class of potent and highly selective antitumor agents has been synthesized. Bisimidazoacridones, where the tetracyclic ring systems are held together by either a N2-methyldiethylenetriamine or 3,3'-diamino-N-methyldipropylamine linker, and related asymmetrical compounds, where one of the imidazoacridone ring system was replaced by a triazoloacridone ring system, were found to be cytostatic and cytotoxic in vitro. Some of these compounds, such as 5,5'-[(methylimino)bis(3,1-propanediylimino)]bis[6H-imidazo[ 4,5,1-de]acridin-6-one] (4b) showed remarkably high activity and selectivity for colon cancer in the National Cancer Institute screen. This antitumor effect was also apparent in colony survival assays utilizing the colon cancer line, HCT-116, and in in vivo assays involving xenografts of tumor derived from HCT-116 in nude mice. The tested compounds exhibited relatively low acute toxicity and were well-tolerated by the treated animals. The bisimidazoacridones interact with nucleic acids in vitro but preliminary experimental and modeling data indicate that in spite of their structure, they may not be bis-intercalators. While the precise mode of action of these compounds is not yet understood, they appear to be excellent candidates for clinical development.
Cholody
W M
WM
Division of Cancer Treatment, National Cancer Institute--Frederick Cancer Research and Development Center, Maryland 21702, USA.
Hernandez
L
L
Hassner
L
L
Scudiero
D A
DA
Djurickovic
D B
DB
Michejda
C J
CJ
D000609:Aminoacridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003196:Computer Graphics; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000609:Aminoacridines; D000970:Antineoplastic Agents; D004247:DNA