Showing papers by "Malcolm F. G. Stevens published in 2007"
TL;DR: It is shown that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, and the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy is revealed.
Abstract: Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.
224 citations
TL;DR: It is reported that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers, and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand.
Abstract: The pentacyclic acridinium methosulfate salt RHPS4 induces the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction.
173 citations
TL;DR: The anticancer activities of these new class of compounds were not similar to that of standard anticancer agents, suggesting novel mechanism(s) of action.
126 citations
TL;DR: Compounds showed selective in vitro inhibition of cancer cell lines of colon and renal origin, a feature of compounds bearing the quinol pharmacophore.
Abstract: Interaction of 2-iodoaniline or 5-fluoro-2-iodoaniline with a range of arylsulfonyl chlorides affords sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne 4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one followed by cyclization to 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclo-hexa-2,5-dien-1-ones This method allows for incorporation of a range of substituents into the arylsulfonyl moiety, and compounds showed selective in vitro inhibition of cancer cell lines of colon and renal origin, a feature of compounds bearing the quinol pharmacophore
43 citations
TL;DR: Three routes have been explored to synthesise the telomere-targeted agent 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate using triethylamine as base and nitrobenzene as solvent.
Abstract: Three routes have been explored to synthesise the telomere-targeted agent 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate 3. Application of a 6-(2-azidophenyl)phenanthridine precursor 11 gave an entry to the indazolo[2,3-f]phenanthridine ring system 12 not the required quino[4,3,2-kl]acridine. A six step synthesis starting from 2,6-dibromo-4-methylbenzonitrile 13via a 1-arylacridin-9(10H)-one intermediate, 19 or 21, gave the required 3 in low overall yield (<10%). The most efficient route entailed the one-pot (five step) conversion of 1,2-dimethyl-6-fluoroquinolinium methosulfate 23 to 3 in 33% yield employing triethylamine as base and nitrobenzene as solvent.
19 citations
TL;DR: Molecular modelling suggested that polar groups appended to the arylsulfonyl residue in indoles 2, which are potential anticancer agents, could aid pharmaceutical properties without adversely affecting activity.
Abstract: Molecular modelling suggested that polar groups appended to the arylsulfonyl residue in indoles 2, which are potential anticancer agents, could aid pharmaceutical properties without adversely affecting activity. A variety of substituted indoles were prepared using a one-pot Sonogashiratype method. A related indole, containing three Michael acceptor groups, has also been prepared.
4 citations