Phenanthroline polyazamacrocycles as G-quadruplex DNA binders

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Phenanthroline polyazamacrocycles as G-quadruplex DNA binders

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Phenanthroline polyazamacrocycles as G-quadruplex DNA binders

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/EF15_003%2F0000477" target="_blank" >EF15_003/0000477: Strukturní gymnastika nukleových kyselin: od molekulárních principů přes biologické funkce k terapeutickým cílům.</a><br>

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Organic & Biomolecular Chemistry

ISSN

1477-0520

e-ISSN

—

Svazek periodika

16

Číslo periodika v rámci svazku

15

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

2776-2786

Kód UT WoS článku

000433442900024

EID výsledku v databázi Scopus

—