title: Synthesis and human telomerase inhibition of a series of regioisomeric disubstituted amidoanthraquinones.
abstract: Telomerase is the enzymatic activity that maintains the ends of eukaryotic chromosomes. Telomerase activity is detected in most tumor cells whereas it is low or undetectable in most normal somatic cells. Expression of the telomerase catalytic component, the human telomerase reverse transcriptase (hTERT), is believed to be controlled primarily at the level of transcription. Because of this selective expression property of telomerase, it has been touted as a specific target for antitumor chemotherapeutics. However, a concern for the applicability of telomerase inhibitors is that they require a long lag time for telomeres to be shortened to critical length before cancer cells stop proliferating. Here we investigate telomerase inhibitory, cytotoxicity and the hTERT repressing effects on a number of synthesized 2,6-diamidoanthraquinones and 1,5-diamidoanthraquinones as compared to their disubstituted homologues. We found that several of the 1,5-diamidoanthraquinones and 2,6-diamidoanthraquinones inhibited telomerase activity effectively with IC50 at the sub-micro to micro molar range and caused acute cytotoxicity to cancer cells with EC50 similar or better than that of mitoxantrone. Particularly, 2,6-diamidoanthraquinone with 2-ethylaminoacetamido side chains 33, even though not affecting cell proliferation, showed to be endowed with a strong telomerase effect, probably related to a marked stabilization of the G-quadruplex-binding structure. The results suggested that these compounds caused multiple effects to cancer cells. More significantly, they overcome the long lag period problem of classical telomerase inhibitors that they are also potent cytotoxic agents. These results greatly expand the potential of tricyclic anthraquinone pharmacophore in preventive and/or curative therapy.
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. huanghs@ndmctsgh.edu.tw
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.forename: In-Been
authors.initials: IB
authors.lastname: Chen
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Huang
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Lu
authors.forename: Fu-Ying
authors.initials: FY
authors.lastname: Shieh
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Huang
authors.forename: Fong-Chun
authors.initials: FC
authors.lastname: Huang
authors.forename: Jing-Jer
authors.initials: JJ
authors.lastname: Lin
mesh_terms: D000577:Amides / Q000737:chemistry*; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D015394:Molecular Structure; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019098:Telomerase