Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors

Schultes, Christoph; Guyen, Bérangère; Cuesta, Javier; Neidle, Stephen

doi:10.1016/j.bmcl.2004.05.090

Cited by 60 publications

(45 citation statements)

References 17 publications

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“…The FRET melting data, given as changes in melting temperature (DT m ) and obtained with fluorescently labelled DNA G4 sequences (0.2 mm) of F21T human telomeric DNA [20] and of oncogene promoter sequences c-Kit2 [7a] and Hsp90A, [5] as well as with T-loop in potassium ion buffer, are summarised in Tables 1 and 2. The results show that the indolo[3,2-b]quinolines 2-4 produce a wide range of G4 stabilisation effects, and, for all compounds, these effects are concentration dependent, with much higher stabilisation effects at 5 mm than at 1 mm, as shown in Figure 2 for 2 e and 4 d (see Supporting Information for the remaining compounds).…”

Section: G-quadruplex Stabilisationmentioning

confidence: 99%

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

et al. 2013

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G‐quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2‐b]quinolines mono‐, di‐, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5‐methyl or a 7‐carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7‐(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter‐G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c‐Kit2, 10‐fold selectivity for G4 over duplex DNA, and 100‐fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.

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Section: G-quadruplex Stabilisationmentioning

confidence: 99%

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

et al. 2013

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“…Cryptolepine is also a rare example of natural product whose preparation was reported before its isolation from natural resource. Recent studies have revealed that some structural derivatives of cryptolepine were capable of interacting with G-quadruplex forms of DNA and inhibiting the activity of telomerase (28,31).…”

Section: Introductionmentioning

confidence: 99%

G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells

Zhou

Deng

Zhang

et al. 2009

Molecular Cancer Therapeutics

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Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci γ-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5-induced γ-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of γ-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5. [Mol Cancer Ther 2009;8 (12):3203-13]

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“…Further mechanistic investigation at the molecular level demonstrated that cryptolepine could interact with DNA through intercalation and interfere with the catalytic activity of topoisomerase II (Bonjean et al, 1998;Lisgarten et al, 2002). Most recent studies further revealed that some structural derivatives of cryptolepine were capable of interacting with G-quadruplex form of DNA and inhibiting the activity of telomerase (Caprio et al, 2000;Schultes et al, 2004). To explore novel and potent telomerase inhibitors for cancer treatment, we have recently designed and synthesized a new series of quindoline analog in our laboratories.…”

Section: Introductionmentioning

confidence: 99%

Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines

Zhou

Zhu

et al. 2005

Oncogene

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Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells., (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC 50 for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.

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Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors

Cited by 60 publications

References 17 publications

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells

Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines

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