Human telomerase inhibition by regioisomeric disubstituted amidoanthracene-9,10-diones.
Telomerase is an attractive target for the design of new anticancer drugs. We have previously described a series of 1,4- and 2, 6-difunctionalized amidoanthracene-9,10-diones that inhibit human telomerase via stabilization of telomeric G-quadruplex structures. The present study details the preparation of three further, distinct series of regioisomeric difunctionalized amidoanthracene-9,10-diones substituted at the 1,5-, 1,8-, and 2,7-positions, respectively. Their in vitro cytotoxicity and Taq DNA polymerase and human telomerase inhibition properties are reported and compared with those of their 1,4- and 2,6-isomers. Potent telomerase inhibition (telIC50 values 1.3-17.3 microM) is exhibited within each isomeric series. In addition, biophysical and molecular modeling studies have been conducted to examine binding to the target G-quadruplex structure formed by the folding of telomeric DNA. These studies indicate that the isomeric diamidoanthracene-9,10-diones bind to the human telomeric G-quadruplex structure with a stoichiometry of 1:1. Plausible G-quadruplex-ligand complexes have been identified for each isomeric family, with three distinct modes of intercalative binding being proposed. The exact mode of intercalative binding is dictated by the positional placement of substituent side chains. Furthermore, in contrast to previous studies directed toward triplex DNA, it is evident that stringent control over positional attachment of substituents is not a necessity for effective telomerase inhibition.
Perry
P J
PJ
Cancer Research Campaign Biomolecular Structure Unit and Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Reszka
A P
AP
Wood
A A
AA
Read
M A
MA
Gowan
S M
SM
Dosanjh
H S
HS
Trent
J O
JO
Jenkins
T C
TC
Kelland
L R
LR
Neidle
S
S
D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002151:Calorimetry; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010051:Ovarian Neoplasms / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019914:Taq Polymerase / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000378:metabolism; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004247:DNA; D019914:Taq Polymerase; D019098:Telomerase