Catecholic flavonoids acting as telomerase inhibitors.
In recent years telomerase has been identified as a new promising target in oncology and consequently new telomerase inhibitors have been intensely explored as anticancer agents. Focused screening of several polyhydroxylated flavonoids has allowed us to identify 7,8,3',4'-tetrahydroxyflavone 1 as a new telomerase inhibitor with an interesting in vitro activity in a Flash-Plate assay (IC50 = 0.2 microM) that has been confirmed in the classical TRAP assay. Starting from this compound, we developed a medicinal chemistry program to optimize our lead, and in particular to replace one of the two catechols with potential bioisosteres. From this study, new structural analogues characterized by submicromolar potencies have been obtained. Their synthesis and biological activity are described.
Menichincheri
Maria
M
Department of Chemistry, BU-Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. maria.menichincheri@nervianoms.com
Ballinari
Dario
D
Bargiotti
Alberto
A
Bonomini
Luisella
L
Ceccarelli
Walter
W
D'Alessio
Roberto
R
Fretta
Antonella
A
Moll
Juergen
J
Polucci
Paolo
P
Soncini
Chiara
C
Tibolla
Marcellino
M
Trosset
Jean-Yves
JY
Vanotti
Ermes
E
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D002396:Catechols; D047309:Flavones; D019098:Telomerase