2,7-disubstituted amidofluorenone derivatives as inhibitors of human telomerase

Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthe...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 42; no. 14; pp. 2679 - 2684
Main Authors: Perry, PJ, Read, MA, Davies, RT, Gowan, SM, Reszka, AP, Wood, AA, Kelland, LR, Neidle, S
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 15.07.1999
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Cell Division - drug effects
Cell Line
Chemistry, Medicinal
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - toxicity
Fluorenes - chemical synthesis
Fluorenes - chemistry
Fluorenes - pharmacology
Fluorenes - toxicity
Humans
Life Sciences & Biomedicine
Models, Molecular
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
Telomerase - antagonists & inhibitors
REVERSE-TRANSCRIPTASE INHIBITORS
THERAPY
MOUSE CELLS LACKING
RNA
QUADRUPLEX DNA
LENGTH
HUMAN FIBROBLASTS
CANCER
CARCINOMA
MOLECULAR MECHANICS
ISSN:0022-2623, 1520-4804
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Summary:Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthesis and biological evaluation of a series of analogous fluorenone-based compounds with the specific aims of, first, determining if the anthraquinone chromophore is a prerequisite for activity and, second, whether the conventional cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad range of telomerase inhibitory activity, with the most potent inhibitors displaying levels of activity (8-12 mu M) comparable with other classes of G-quadruplex-interactive agents. Comparisons with analogous anthraquinone-based compounds reveal a general reduction in the level of cellular cytotoxicity. Molecular modeling techniques have been used to compare the interaction of fluorenone- and analogous anthraquinone-based inhibitors with a human G-quadruplex structure and to rationalize their observed biological activities.
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm990084q