A new synthetic agent with potent but selective cytotoxic activity against cancer.
The synthesis of novel unsymmetrical bifunctional antitumor agents was accomplished by linking an imidazoacridone moiety to another polycyclic heteroaromatic moiety via linkers of various length and rigidity. These compounds bind to cellular DNA, but it is hypothesized that biological effects become manifested when the drug-DNA complexes interact with critical DNA binding proteins that are involved in repair and transcription. The most promising compound of the series, 4ad (WMC79), consists of an imidazoacridone linked to a 3-nitronaphthalimide moiety via a 1,4-dipropanopiperazine linker. It was found to be potently, but selectively, cytotoxic against colon cancers (GI(50) = 0.5 nM, LC(50) = 32 nM) and leukemias (GI(50) = 3.5 nM, LC(50) = 33 nM). Compound 4ad, which appears to be a candidate for further development as an anticancer drug, kills sensitive cells by induction of apoptosis. It also showed significant in vivo activity against HCT-116 colon cancer xenografts in nude mice. Other compounds in the series also exhibited antitumor properties, but they were significantly lower than that of 4ad.
Cholody
Wieslaw M
WM
Molecular Aspects of Drug Design, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
Kosakowska-Cholody
Teresa
T
Hollingshead
Melinda G
MG
Hariprakasha
Humcha K
HK
Michejda
Christopher J
CJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D018288:Carcinoma, Small Cell; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D008175:Lung Neoplasms
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm