1,4- and 2,6-Disubstituted Amidoanthracene-9,10-dione Derivatives as Inhibitors of Human Telomerase

Abstract

A number of 1,4- and 2,6-difunctionalized amidoanthracene-9, 10-diones have been prepared. We have examined their in vitro cytotoxicity in several tumor cell lines and their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. Compounds with -(CH2)2- side chains terminating in basic groups such as piperidine show inhibition of telomerase at telIC50 levels of 4-11 microM. These are thus among the most potent nonnucleoside telomerase inhibitors reported to date. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Implications for amidoanthracene-9,10-dione telomerase inhibitors as potential anticancer agents are discussed.

Studies on Anthracenes. 1. Human Telomerase Inhibition and Lipid Peroxidation of 9-Acyloxy 1,5-Dichloroanthracene Derivatives.

“…Prior to the evaluation of compounds in the PCRbased telomerase assay, the agents were tested for their ability to inhibit Taq polymerase in order to address the selectivity of polymerase/telomerase inhibition. 10,[16][17][18] Approximately most of the compounds examined completely inhibited Taq polymerase activity at concentration of 1 mM, 0.1 mM, and 0.01 mM, respectively, whereas 3b, 3d, 3g, 3h, 3k, and 3w, showed significant inhibitory effect at the three different concentrations. Further, there does not appear to be any correlation between Taq polymerase inhibition and cytotoxicity.…”

“…Taq Polymerase Assay 10,[16][17][18] Compounds were included at both 10 and 50 mM final concentrations in a PCR 50 ml master mix comprising 10 ng of pCI-neo mammalian expression vector (Promega, Southampton, U.K.), forward (GGAGTTCCGCGT-TACATAAC) and reverse (GTCTGCTC-GAAGCATTAACC) primers (200 nmol), reaction buffer (75 mM Tris-HCl, pH 8.8, 20 mM (NH 4 ) 2 SO 4 , 0.01% v/v Tween 20), 2.5 mM MgCl 2 , 200 mM of each deoxynucleotide triphosphate, and thermostable DNA polymerase ("red hot", Advanced Biotechnologies) 1.25 units. A reaction mix containing water and no drug was used as a positive control, producing a product of approximately 1 kb.…”

Synthesis and Antitumor Evaluation of Symmetrical 1,5-Diamidoanthraquinone Derivatives as Compared to Their Disubstituted Homologues

“…8,[18][19][20] In addition, biophysical studies on a range of side arms and structure-activity relationships have been conducted in order to examine binding to the proposed target structure formed by the cytotoxicity and telomerase inhibition.…”

“…[1][2][3][4][5][6][7][8] Antineoplastic drugs generally have a narrow therapeutic index and are delivered at doses close to toxicity. Despite extensive and long-standing clinical utilization, the mechanisms responsible for the antiproliferative and cytotoxic effects of anthracycline antibiotic doxorubicin are still uncertain and have been the subject of considerable controversy.…”

“…[3][4][5][6]14) Their in vitro cytotoxicity was reported and compared with those of their isomers, and it was proposed that their activity may be due to their ability to bind to and stabilize G-quadruplex structures. 8,15) The positional attachment and character of the diacyloxy-, dithio-, diamino-, and diamido side chains have been shown to profoundly influence their mode of DNA binding and cytotoxicity. For example, 1,4-diamidoanthraquinones have been shown to bind to duplex DNA by classical intercalation, 16) whereas their cytotoxicity and human telomerase inhibition, 5,14) in which the different functionalized side chains may simultaneously occupy both the DNA major and minor grooves, with intercalation of the planar chromophore.…”