Phenanthroline polyazamacrocycles as G-quadruplex DNA binders

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00492329" target="_blank" >RIV/68081707:_____/18:00492329 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1039/c8ob00247a" target="_blank" >http://dx.doi.org/10.1039/c8ob00247a</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c8ob00247a" target="_blank" >10.1039/c8ob00247a</a>

Result language

angličtina

Original language name

Phenanthroline polyazamacrocycles as G-quadruplex DNA binders

Original language description

Targeting quadruplex DNA structures with small molecules is a promising strategy for anti-cancer drug design Four phenanthroline polyazamacrocycles were studied for their binding affinity, thermal stabilization, inhibitory effect on the activity of helicase towards human telomeric 22AG and oncogene promoter c-MYC G-quadruplexes (G4s), and their ability to inhibit Taq polymerase-mediated DNA extension The fluorescence resonance energy transfer (FRET) melting assay indicates that the melting temperature increases (Delta T-m values) of c-MYC and 22AG G4s are 17.2 and 20.3 C-degrees, respectively, for the ligand [32] phen(2)N(4) followed by [16]phenN(4) (11.3 and 15.0 C-degrees, for c-MYC and 22AG, respectively). Competitive FRET assays show that [32]phen(2)N(4) and [16]phenN(4) exhibit G4 selectivity over duplex DNA. Different G4s were compared, no considerable selectivity of the ligands for a specific G4 was found. Circular dichroism (CD) confirms the formation of G4 structures and the melting experiments show that [16]phenN(4) and [32] phen(2)N(4) are the most stabilizing ligands with a Delta T-m of 19.3 C-degrees and 15.1 C-degrees, respectively, at 5 molar equivalents for the c-MYC G4. The fluorescent intercalator displacement (FID) assay also demonstrates that ligand [32]phen(2)N(4) furnishes very low DC50 values (0.87-1.24 mu M), indicating high stabilization of c-MYC and 22AG G4s. These results suggest that the hexyl chain in these compounds plays an important role in regulating the stabilization of these G4s. Binding constants, determined by fluorescence titrations, indicate a moderate ligand-G4 binding with K-sv between 105 and 10(6) M-1 in which [16]phenN(4) has a slightly higher apparent binding constant for telomeric 22AG G4 than that for the c-MYC G4. The ligand's ability to inhibit Taq polymerase confirms the biological activity of [16]phenN(4) and [32]phen(2)N(4) against the c-MYC G4. In addition, ligands [32]phen(2)N(4) and [16]phenN(4) affect the unwinding activity of Pif1 in the presence of DNA systems harboring c-MYC and telomeric G4 motifs.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10401 - Organic chemistry

Project

<a href="/en/project/EF15_003%2F0000477" target="_blank" >EF15_003/0000477: Structural gymnastics of nucleic acids: from molecular principles through biological functions to therapeutic targets.</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Organic & Biomolecular Chemistry

ISSN

1477-0520

e-ISSN

—

Volume of the periodical

16

Issue of the periodical within the volume

15

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

2776-2786

UT code for WoS article

000433442900024

EID of the result in the Scopus database

—