Quadruplex-Interactive Agents as Telomerase Inhibitors:  Synthesis of Porphyrins and Structure−Activity Relationship for the Inhibition of Telomerase

Shi, Decheng; Wheelhouse, Richard T.; Sun, Daekyu; Hurley, Laurence H.

doi:10.1021/jm010246u

Cited by 246 publications

(174 citation statements)

References 58 publications

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“…The number of G4 ligands has grown rapidly over a few years: a range of molecules has been shown to inhibit telomerase through binding to its substrate [14,26,27,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. On the other hand, few natural products have been reported as G-quadruplex-mediated telomerase inhibitors, although one, telomestatin, is exceptionally potent with an IC50 of 5 nM against telomerase [25].…”

Section: Discussionmentioning

confidence: 99%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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Ascididemin and Meridine are two marine compounds with pyridoacridine skeletons known to exhibit interesting antitumour activities. These molecules have been reported to behave like DNA intercalators. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of ascididemin and meridine for DNA structures among duplexes, triplexes, quadruplexes and single-strands. Our data confirm that ascididemin and meridine interact with DNA but also recognize triplex and quadruplex structures. These molecules exhibit a significant preference for quadruplexes over duplexes or single-strands. Meridine is a stronger quadruplex ligand and therefore a stronger telomerase inhibitor than ascididemin (IC 50 =ll and >80 µM, respectively in a standard TRAP assay).

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Section: Discussionmentioning

confidence: 99%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…This makes telomerase a target not only for cancer diagnosis but also for the development of novel therapeutic agents (Bearss et al, 2000). One effective strategy for the design of telomerase inhibitors targets telomerase indirectly, via the telomeric substrate, and aims to block the interaction between the enzyme and the telomere (Shi et al, 2001). At the extreme 3 0 -termini of the telomeres, there are regions of single-stranded DNA, formed because of a limitation of the DNA polymerization mechanism, the end replication problem.…”

Section: Introductionmentioning

confidence: 99%

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

et al. 2003

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The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABLpositive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 lm; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21 CIP1 and p27 KIP1 . These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

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“…With a few notable exceptions (6,(9)(10)(11)(12), TRAP [or a variant called TRAP-G4 (13)] has been the standard method to measure telomerase inhibition by G-quadruplex ligands (reviewed in ref. 7).…”

mentioning

confidence: 99%

Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action

Cian

Cristofari

Reichenbach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

268

193

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Quadruplex ligands are often considered as telomerase inhibitors. Given the fact that some of these molecules are present in the clinical setting, it is important to establish the validity of this assertion. To analyze the effects of these compounds, we used a direct assay with telomerase-enriched extracts. The comparison of potent ligands from various chemical families revealed important differences in terms of effects on telomerase initiation and processivity. Although most quadruplex ligands may lock a quadruplex-prone sequence into a quadruplex structure that inhibits the initiation of elongation by telomerase, the analysis of telomerase-elongation steps revealed that only a few molecules interfered with the processivity of telomerase (i.e., inhibit elongation once one or more repeats have been incorporated). The demonstration that these molecules are actually more effective inhibitors of telomeric DNA amplification than extension by telomerase contributes to the already growing suspicion that quadruplex ligands are not simple telomerase inhibitors but, rather, constitute a different class of biologically active molecules. We also demonstrate that the popular telomeric repeat amplification protocol is completely inappropriate for the determination of telomerase inhibition by quadruplex ligands, even when PCR controls are included. As a consequence, the inhibitory effect of many quadruplex ligands has been overestimated.G-quadruplex ͉ telomere ͉ telomeric repeat amplification protocol assay ͉ direct assay T he unlimited proliferative potential of cancer cells depends on telomere maintenance (1). As a consequence, several classes of telomerase inhibitors have been developed for anticancer purposes. Optimal telomerase activity requires an unfolded single-stranded telomeric overhang (2-4). This overhang may adopt an unusual DNA structure called a G-quadruplex, composed of G-quartets and formed in the presence of cations (5). Therefore, ligands that selectively bind to and stabilize telomeric G-quadruplex structures could act as indirect telomerase inhibitors (Fig. 1A) (6). The number of identified G-quadruplex ligands has grown rapidly over the past few years (for a recent review, see ref. 7); some of these molecules exhibit potent in vivo antitumor activity, and clinical trials started recently.Although various methods are available to measure telomerase activity, the telomeric repeat amplification protocol (TRAP) is most widely used (8). With a few notable exceptions (6, 9-12), TRAP [or a variant called TRAP-G4 (13)] has been the standard method to measure telomerase inhibition by G-quadruplex ligands (reviewed in ref. 7). The original method was improved by the use of an internal control (often called ITAS for internal telomerase assay standard) that coamplifies with the telomerase products and allows the detection of nonspecific Taq polymerase inhibitors. Notably, the ITAS product does not contain any telomeric sequence and therefore is not able to form a G-quadruplex (5,14). We demonstrate here that TRAP is...

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Quadruplex-Interactive Agents as Telomerase Inhibitors: Synthesis of Porphyrins and Structure−Activity Relationship for the Inhibition of Telomerase

Cited by 246 publications

References 58 publications

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action

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