Repositorio
Institucional

Salas, Cristian O.

Bertrand, Jeanluc

Dostalova, Hana

Krystof, Vladimir

Jorda, Radek

Delgado, Thalia

Castro-Alvarez, Alejandro

Mella, Jaime

Cabezas, David

Faundez, Mario

Espinosa-Bustos, Christian

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

MDPI

PHARMACEUTICS

en

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 mu M for BTK) and 5b (IC50 = 0.38 mu M for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs.

artículo original

This research was funded by the Czech Science Foundation (21-06553S), Palacky University in Olomouc (IGA_PrF_2022_007) and the European Regional Development Fund (Project ENOCH, No. CZ.02.1.01/0.0/0.0/16_019/0000868) and CONICYT-CHILE for the PhD fellowship Nffi 21180975.

Esta investigación fue financiada por la Fundación Checa de Ciencias (21-06553S), la Universidad Palacky en Olomouc (IGA_PrF_2022_007) y el Fondo Europeo de Desarrollo Regional (Proyecto ENOCH, No. CZ.02.1.01/0.0/0.0/16_019/0000868) y CONICYT -CHILE para la beca de doctorado Nffi 21180975.

10.3390/pharmaceutics14061294

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leukaemia

purine derivatives

tyrosine kinases inhibitors

3D-QSAR

molecular docking

X-LINKED AGAMMAGLOBULINEMIA

HEMATOLOGIC MALIGNANCIES

KINASE

RESISTANT

IMATINIB

MUTATIONS

VALIDATION

STRATEGIES

BMS-354825

APOPTOSIS

Farmacología y farmacia

leucemia

derivados de purina

inhibidores de tirosina quinasas

3D-QSAR

acoplamiento molecular

AGAMMAGLOBULINEMIA LIGADA AL X

MALIGNANCIAS HEMATOLOGICAS

QUINASA

RESISTENTE

IMATINIB

MUTACIONES

VALIDACIÓN

ESTRATEGIAS

BMS-354825

APOPTOSIS

Química Orgánica

Farmacología y Farmacia

Oncología

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

artículo original

version publicada

CC BY 4.0

CC BY 4.0

acceso abierto

acceso abierto

GACR 21-06553S

UPOL IGA_PrF_2022_007

UE CZ.02.1.01/0.0/0.0/16_019/0000868

ANID 21180975

WOS:000816420600001