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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Vydáno v:	Journal of medicinal chemistry Ročník 42; číslo 14; s. 2679 - 2684
Hlavní autoři:	Perry, PJ, Read, MA, Davies, RT, Gowan, SM, Reszka, AP, Wood, AA, Kelland, LR, Neidle, S
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	WASHINGTON Amer Chemical Soc 15.07.1999
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm990084q