Adamantane-Substituted Purines and Their beta-Cyclodextrin Complexes: Synthesis and Biological Activity
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F21%3A73610775" target="_blank" >RIV/61989592:15310/21:73610775 - isvavai.cz</a>
Výsledek na webu
<a href="https://www.mdpi.com/1422-0067/22/23/12675/htm" target="_blank" >https://www.mdpi.com/1422-0067/22/23/12675/htm</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/ijms222312675" target="_blank" >10.3390/ijms222312675</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Adamantane-Substituted Purines and Their beta-Cyclodextrin Complexes: Synthesis and Biological Activity
Popis výsledku v původním jazyce
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that beta-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with beta-CD.
Název v anglickém jazyce
Adamantane-Substituted Purines and Their beta-Cyclodextrin Complexes: Synthesis and Biological Activity
Popis výsledku anglicky
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that beta-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with beta-CD.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10608 - Biochemistry and molecular biology
Návaznosti výsledku
Projekt
<a href="/cs/project/GA19-08410S" target="_blank" >GA19-08410S: Substituované imidazopyrimidiny: Racionální návrh a vývoj specifických inhibitorů proteinkinas s protinádorovým účinkem</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2021
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
1422-0067
e-ISSN
—
Svazek periodika
22
Číslo periodika v rámci svazku
23
Stát vydavatele periodika
CH - Švýcarská konfederace
Počet stran výsledku
20
Strana od-do
"12675-1"-"12675-20"
Kód UT WoS článku
000735654100001
EID výsledku v databázi Scopus
2-s2.0-85119661216