Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity

M. Rouchal, J. Rudolfová, V. Kryštof, V. Vojáčková, R. Čmelík, R. Vícha

. 2021 ; 22 (23) : . [pub] 20211124

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22003169

Grant support
IGA/FT/2021/001 Tomas Bata University in Zlín

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 β-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 β-CD.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22003169
003      
CZ-PrNML
005      
20220127150617.0
007      
ta
008      
220113s2021 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/ijms222312675 $2 doi
035    __
$a (PubMed)34884480
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a Rouchal, Michal $u Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech Republic
245    10
$a Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity / $c M. Rouchal, J. Rudolfová, V. Kryštof, V. Vojáčková, R. Čmelík, R. Vícha
520    9_
$a 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 β-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 β-CD.
650    _2
$a adamantan $x chemie $7 D000218
650    _2
$a protinádorové látky $x chemie $x farmakologie $7 D000970
650    _2
$a cyklin-dependentní kinasa 2 $x antagonisté a inhibitory $7 D051357
650    _2
$a lidé $7 D006801
650    _2
$a buňky K562 $7 D020014
650    _2
$a MFC-7 buňky $7 D061986
650    _2
$a inhibitory proteinkinas $x farmakologie $7 D047428
650    _2
$a puriny $x chemie $7 D011687
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
650    _2
$a beta-cyklodextriny $x chemie $7 D047392
655    _2
$a časopisecké články $7 D016428
700    1_
$a Rudolfová, Jana $u Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech Republic
700    1_
$a Kryštof, Vladimír $u Department of Experimental Biology, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
700    1_
$a Vojáčková, Veronika $u Department of Experimental Biology, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
700    1_
$a Čmelík, Richard $u Institute of Analytical Chemistry of the Czech Academy of Sciences, Veveří 97, 602 00 Brno, Czech Republic
700    1_
$a Vícha, Robert $u Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech Republic
773    0_
$w MED00176142 $t International journal of molecular sciences $x 1422-0067 $g Roč. 22, č. 23 (2021)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34884480 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220113 $b ABA008
991    __
$a 20220127150613 $b ABA008
999    __
$a ok $b bmc $g 1750818 $s 1154318
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 22 $c 23 $e 20211124 $i 1422-0067 $m International journal of molecular sciences $n Int J Mol Sci $x MED00176142
GRA    __
$a IGA/FT/2021/001 $p Tomas Bata University in Zlín
LZP    __
$a Pubmed-20220113

Find record

Citation metrics

Archiving options