Human telomerase inhibition and cytotoxicity of regioisomeric disubstituted amidoanthraquinones and aminoanthraquinones.
Telomerase is an attractive target for the rational design of new anticancer drugs due to its central role in the control of cellular proliferation. A number of 1,4-disubstituted amidoanthraquinones and 1,5-disubstituted aminoanthraquinones that are related to mitoxantrone and ametantrone have previously been prepared. The present study details the effects on human telomerase of these new classes of 1,4- and 1,5-difunctionalized tricyclic anthraquinone compounds. We have used cytotoxicity assay, reporter SEAP assay to monitor the hTERT expression, and TRAP-G4 assay to measure the relative activity of these compounds, and have examined how the attached substituents affect their ability to influence telomerase. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Structural and activity relationships indicated that the position of disubstituent side chains is important for its inhibitory effect. Moreover, a primary amine or tertiary amine on the substitution group appears to be required for the telomerase inhibitory effect. There is no significant correlation between telomerase activity and cytotoxicity. These symmetrical disubstituted anthraquinones may represent useful leads for the development of human telomerase inhibitors as potential anticancer agents, and the exact mode of intercalative binding is dictated by the positional placement of substituent side chains for effective telomerase inhibition.
Huang
Hsu-Shan
HS
School of Pharmacy, National Defense Medical Center, Neihu, Taipei 114, Taiwan ROC. huanghs@ndmctsgh.edu.tw
Chou
Chung-Long
CL
Guo
Ching-Long
CL
Yuan
Chun-Lung
CL
Lu
Yu-Cheng
YC
Shieh
Fu-Ying
FY
Lin
Jing-Jer
JJ
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D019098:Telomerase / Q000037:antagonists & inhibitors*
D000577:Amides; D000588:Amines; D000880:Anthraquinones; D004791:Enzyme Inhibitors; D019098:Telomerase