Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands

Ohnmacht, Stephan A.; Ciancimino, Cristina; Vignaroli, Giulia; Gunaratnam, Mekala; Neidle, Stephen

doi:10.1016/j.bmcl.2013.07.057

Cited by 9 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Also, regioisomeric compound 25 and naphthalene bis‐oxazole 26 do not significantly increase the T m values of several DNA G4 sequences . The naphthalene bis‐oxazole analogue with a side chain in the meta position (i.e., compound 26 ) is also a weak G4 ligand . Despite their low G4 binding affinities, compounds with the side chain in the meta position (i.e., compounds 24 ) show IC 50 values against four cancer cell lines and one fibroblast cell line in the low micromolar range …”

Section: The Search For the Best Ligand Shapementioning

confidence: 99%

Design of Modular G‐quadruplex Ligands

et al. 2018

View full text Add to dashboard Cite

Guanine-rich nucleic acid sequences able to form four-stranded structures (G-quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure-G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.

show abstract

Section: The Search For the Best Ligand Shapementioning

confidence: 99%

Design of Modular G‐quadruplex Ligands

et al. 2018

View full text Add to dashboard Cite

show abstract

“…91 More recently, Neidle and co-workers discovered that compound 146 exhibited significant broad spectrum antiproliferative activity in a panel of human carcinoma cell lines. 93 They also identified bis-oxazole 152, possessing a central phenyl ring and two oxazole rings meta-attached to phenyl rings, as a derivative with optimized anti-proliferative activity. Compound 152 was synthesized by reacting bis-oxazole 149 with aryl bromide 151 in toluene at 110 °C in the presence of K 2 CO 3 and a catalyst system consisting of a mixture of Pd(OAc) 2 , pivalic acid and RuPhos (Scheme 34).…”

Section: Scheme 33mentioning

confidence: 99%

“…Unfortunately, the yield of the reaction was not reported, but it was described that compound 152 was capable of stabilizing several quadruplex DNA sequences including a human telomeric DNA. 93 In 2011, Itami and co-workers developed novel Ni-based catalyst systems for the direct C2-arylation of azoles with aryl halides and applied these systems to the synthesis of biologically active compounds. 94 One of these catalyst systems, which was formed by a mixture of Ni(cod) 2 , 2,2′-bipyridyl (bipy) and LiOt-Bu, was used in a concise synthesis of tafamidis (153) (Figure 17…”

Section: Scheme 33mentioning

confidence: 99%

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

et al. 2016

View full text Add to dashboard Cite

The significant number of papers and reviews published in this last decade testifies to the utility of the transition-metal-catalyzed direct C–H (hetero)arylation reactions of (hetero)arenes as efficient and powerful tools for the step- and atom-economical, regio- and chemoselective synthesis of natural and unnatural compounds. However, no review has so far been devoted to summarizing the application of these reactions in the synthesis of biologically active compounds. This review with 341 references aims to fill this gap, providing a comprehensive picture of the transition-metal-catalyzed intra- and intermolecular direct C–H (hetero)arylation reactions of (hetero)arenes with (hetero)aryl halides or pseudohalides that have been used as key steps of syntheses of unnatural biologically relevant compounds including pharmaceutical targets, up to the end of September 2015. Attention has also been directed to provide a brief description of the biological properties of the synthesized compounds. 1 Introduction 2 Syntheses via Intramolecular Direct (Hetero)arylation of (Hetero)arene Derivatives 3 Syntheses via Intermolecular Direct (Hetero)arylation Reactions 3.1 Of Arenes 3.2 Of Five-Membered Heteroarenes with One Heteroatom 3.3 Of Five-Membered Heteroarenes with Two Heteroatoms 3.4 Of Five-Membered Heteroarenes with Three and Four Heteroatoms 3.5 Of Five-Membered Heteroarenes Fused to a Six-Membered Heteroarene 3.6 Of Five-Membered Heteroarene Moieties of Tricyclic Heteroarenes 3.7 Of Six-Membered Heteroarenes 4 Syntheses of Nitrogen-Containing Polycyclic Heteroarene via One-Pot Palladium-Catalyzed Domino Direct Arylation/N-Arylation Reactions 5 Conclusion

show abstract

“…The G-quadruplex, stabilized by Hoogsteen hydrogen bonds, is one of the most important secondary structures of nucleic acids, and forms in G-rich sequences under some monovalent cations. 1 These special secondary structures are present in important regions of the eukaryotic genome, such as telomeres and the regulatory regions of several genes; therefore such structures play important roles in the regulation of biological events. [2][3][4][5] In recent years, the G-quadruplex has attracted intense interest because of its potential biological functions, such as gene regulation, gene expression and antitumor potential.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage

Franceschin

Nocioni

Biroccio³

et al. 2014

Org. Biomol. Chem.

View full text Add to dashboard Cite

Following the results we previously reported on a series of xanthene and xanthone derivatives as G-quadruplex stabilizing ligands, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand, specifically its aromatic extension. In particular, here we report the design, synthesis and activity data of a new compound obtained by dimerization of the xanthene core (HELIXA4C). The reported results show that extension of the aromatic core and the increase of the number of polar side chains led to a great enhancement of G-quadruplex selectivity and telomere damage capability, as derived using ESI-MS evaluation, in vitro cancer screening and specific immunofluorescence assays.

show abstract

Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands

Cited by 9 publications

References 33 publications

Design of Modular G‐quadruplex Ligands

Design of Modular G‐quadruplex Ligands

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage

Contact Info

Product

Resources

About