Hybrid ligand–alkylating agents targeting telomeric G-quadruplex structures

Doria, Filippo; Nadai, Matteo; Folini, Marco; Antonio, Marco Di; Germani, Luca; Percivalle, Claudia; Sissi, Claudia; Zaffaroni, Nadia; Alcaro, Stefano; Artese, Anna; Richter, Sara N.; Freccero, Mauro

doi:10.1039/c2ob06816h

Cited by 93 publications

(90 citation statements)

References 41 publications

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“…As previously reported, H-NDI-NMe 2 derivative exerted an inhibitory effect on the catalytic activity of telomerase in sKMel-5 cells that seemed to primarily occur as a consequence of drug-mediated decrease of TERT and MYC mRNA expression levels (21). To further investigate the capability of the compound to interfere with the expression of selected genes, we focused on TERT, MYC, KIT and BCL2, which have been reported to undergo inhibition following ligand-mediated stabilization of G-4 structures within their promoters (8).…”

Section: Resultsmentioning

confidence: 54%

“…1a) that displays high affinity and stabilization properties towards the human telomeric sequence (21). In addition, H-NDI-NMe 2 was able to significantly impair melanoma cell growth by causing telomere dysfunction and inhibition of telomerase activity, likely as a consequence of its interference with the expression levels of MYC and TERT (21).…”

Section: Introductionmentioning

confidence: 98%

“…The functionalized naphthalene diimide H-NDI-NMe 2 was synthesized, characterized, and purified according to a published protocol, optimized by our group (21).…”

Section: Methodsmentioning

confidence: 99%

“…To date, a diverse array of G-4 stabilizing compounds has been identified (17,18). Among them, numerous tri-and tetra-substituted naphthalene diimides (NDIs) have shown high affinity for telomeric G-4s and good antiproliferative activity in different experimental human tumor models (19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Nadai

Cimino‐Reale

Sattin

et al. 2014

International Journal of Oncology

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Abstract. naphthalene diimide (nDi) derivatives have shown high affinity for telomeric guanine (G)-quadruplexes and good antiproliferative activity in different human tumor experimental models. A trisubstituted compound (H-NDI-NMe 2 ) has been reported to stabilize the telomeric G-quadruplex and to cause telomere dysfunction and downregulation of telomerase expression. We further investigated its mechanism of action by analyzing the capability of the molecule to interfere with the expression levels of oncogenes, such as MYC, telome rase reverse transcriptase (TERT), KIT and BCL2, known to bear G-quadruplex-forming sequences within their promoters, in human tumor cell lines of different histological origin. Exposure to H-NDI-NMe 2 resulted in a cell type-dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H-NDI-NMe 2 bound with high affinity and effectively stabilized mainly MYC and BCL2, which share long sequences and the possibility of multiple G-quadruplex folding. The mRNA levels of both genes, but not protein amounts were affected by NDI treatment. Global gene expression analysis showed modulation of genes implicated in telomere function and mechanisms of cancer; however, G-quadruplex-mediated regulation of gene expression by H-NDI-NMe 2 was largely dependent on the cell context. These data indicate that a deeper knowledge on the molecular mechanisms and biological effects of G-quadruplex structures is still needed to help developing new effective anticancer agents.

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Section: Resultsmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 98%

“…The functionalized naphthalene diimide H-NDI-NMe 2 was synthesized, characterized, and purified according to a published protocol, optimized by our group (21).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Nadai

Cimino‐Reale

Sattin

et al. 2014

International Journal of Oncology

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“…In studies, indole, benzimidazole and quinazoline rings have been used as precursors of quinone methides because of their excessive reactivity [14][15][16][17] . Reversibly binding to nucleophilic sites on telomeric DNA via Michael addition reaction is thought to be responsible for the anticancer activity of both of a-methylene-g-lactone and quinone methide chemical groups [18][19][20][21] . In the light of these studies and as an extension of our previous works on anticancer active pyrazino[1,2-a]benzimidazole derivatives [22][23][24] , we now report on the synthesis and the anticancer activity testing of some 2-benzyl-1-methylidene-3-phenyl-1,2-dihydropyrazino[1,2-a]benzimidazole derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives

Demirayak¹,

Yurttaş²

2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The synthesis of some new pyrazino[1,2-a]benzimidazole derivatives and investigation of their anticancer activities were aimed in this work. Thus, 2-acetylbenzimidazole was reacted with appropriate a-bromoacetophenones and potassium carbonate in acetone to give 2-(2-acetyl-1H-benzimidazol-1-yl)-1-phenylethanone derivatives (3a-d). These diketone compounds were reacted with varied benzylamines in acetic acid to obtain 2-benzyl-1-methylidene-3-aryl-1,2-dihydropyrazino[1,2-a]benzimidazole derivatives (4a-t). The structures of the obtained compounds were elucidated by using IR, 1

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Photo‐Cross‐Linking Probes for Trapping G‐Quadruplex DNA

et al. 2013

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We have developed a straightforward synthetic pathway to a set of six photoactivatable G-quadruplex ligands with a validated G4-binding motif (the bisquinolinium pyridodicarboxamide PDC-360A) tethered through various spacers to two different photo-cross-linking groups: benzophenone and an aryl azide. The high quadruplex-versusduplex selectivity of the PDC core was retained in the new derivatives and resulted in selective alkylation of two wellknown G-quadruplexes (human telomeric G4 and oncogene promoter c-myc G4) under conditions of harsh competition. The presence of two structurally different photoactivatable functions allowed the selective alkylation of G-quadruplex structures at specific nucleobases and irreversible G4 binding. The topology and sequence of the quadruplex matrix appear to influence strongly the alkylation profile, which differs for the telomeric and c-myc quadruplexes. The new compounds are photoactive in cells and thus provide new tools for studying G4 biology.

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Hybrid ligand–alkylating agents targeting telomeric G-quadruplex structures

Cited by 93 publications

References 41 publications

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives

Photo‐Cross‐Linking Probes for Trapping G‐Quadruplex DNA

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