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

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

C. O Salas, AM. Zarate, V. Kryštof, J. Mella, M. Faundez, J. Brea, MI. Loza, I. Brito, D. Hendrychová, R. Jorda, AR. Cabrera, RA. Tapia, C. Espinosa-Bustos,

. 2019 ; 21 (1) : . [pub] 20191225

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc20023310

Grant support
1161816 Fondo Nacional de Desarrollo Científico y Tecnológico
NV17-31834A MZ0 CEP Register

We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20023310
003      
CZ-PrNML
005      
20201214125723.0
007      
ta
008      
201125s2019 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/ijms21010161 $2 doi
035    __
$a (PubMed)31881717
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a O Salas, Cristian $u Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
245    10
$a Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays / $c C. O Salas, AM. Zarate, V. Kryštof, J. Mella, M. Faundez, J. Brea, MI. Loza, I. Brito, D. Hendrychová, R. Jorda, AR. Cabrera, RA. Tapia, C. Espinosa-Bustos,
520    9_
$a We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.
650    _2
$a protinádorové látky $x chemická syntéza $x chemie $x farmakologie $7 D000970
650    _2
$a apoptóza $x účinky léků $7 D017209
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a krystalografie rentgenová $7 D018360
650    _2
$a screeningové testy protinádorových léčiv $7 D004354
650    _2
$a lidé $7 D006801
650    _2
$a molekulární konformace $7 D008968
650    _2
$a puriny $x chemická syntéza $x chemie $x farmakologie $7 D011687
650    12
$a kvantitativní vztahy mezi strukturou a aktivitou $7 D021281
650    _2
$a kontrolní body fáze S buněčného cyklu $x účinky léků $7 D059807
655    _2
$a časopisecké články $7 D016428
700    1_
$a Zarate, Ana Maria $u Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
700    1_
$a Kryštof, Vladimir $u Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
700    1_
$a Mella, Jaime $u Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, 2360102, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso, Casilla 5030, Chile.
700    1_
$a Faundez, Mario $u Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
700    1_
$a Brea, Jose $u Innopharma Screening Platform-BioFarma Research Group, Centre for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela 15706, Spain.
700    1_
$a Loza, María Isabel $u Innopharma Screening Platform-BioFarma Research Group, Centre for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela 15706, Spain.
700    1_
$a Brito, Ivan $u Departamento de Química, Facultad de Ciencias Básicas, Universidad de Antofagasta, Av. Angamos 601, Antofagasta 1240000, Chile.
700    1_
$a Hendrychová, Denisa $u Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
700    1_
$a Jorda, Radek $u Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71 Olomouc, Czech Republic. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinská 5, 77900 Olomouc, Czech Republic.
700    1_
$a Cabrera, Alan R $u Departamento de Química Inorgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
700    1_
$a Tapia, Ricardo A $u Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
700    1_
$a Espinosa-Bustos, Christian $u Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile.
773    0_
$w MED00176142 $t International journal of molecular sciences $x 1422-0067 $g Roč. 21, č. 1 (2019)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31881717 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20201125 $b ABA008
991    __
$a 20201214125722 $b ABA008
999    __
$a ok $b bmc $g 1595629 $s 1113986
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 21 $c 1 $e 20191225 $i 1422-0067 $m International journal of molecular sciences $n Int J Mol Sci $x MED00176142
GRA    __
$a 1161816 $p Fondo Nacional de Desarrollo Científico y Tecnológico
GRA    __
$a NV17-31834A $p MZ0
LZP    __
$a Pubmed-20201125

Find record

Citation metrics

Archiving options