Effects of 1,3,5-triphenyl-4,5-dihydro-1H-pyrazole derivatives on cell-cycle and apoptosis in human acute leukemia cell lines.
Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Lorena Dos
LD
Santos Bubniak
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Pâmela Cristina
PC
Gaspar
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Ana Carolina Rabello
ACR
de Moraes
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Alisson
A
Bigolin
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Rubia Karine
RK
de Souza
c Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale de Itajaí, UNIVALI, CEP - Itajaí, Santa Catarina, Brazil.
Fátima Campos
FC
Buzzi
c Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale de Itajaí, UNIVALI, CEP - Itajaí, Santa Catarina, Brazil.
Rogério
R
Corrêa
c Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale de Itajaí, UNIVALI, CEP - Itajaí, Santa Catarina, Brazil.
Valdir Cechinel
VC
Filho
b Departamento de Química, Universidade Federal de Santa Catarina, UFSC, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Lizandra Czermainski
LC
Bretanha
b Departamento de Química, Universidade Federal de Santa Catarina, UFSC, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Gustavo Amadeu
GA
Micke
b Departamento de Química, Universidade Federal de Santa Catarina, UFSC, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Ricardo José
RJ
Nunes
a Departamento de Análises Clínicas, Universidade Federal de Santa Catarina - UFSC, 89, Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Maria Cláudia
MC
Santos-Silva
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001777:Blood Coagulation / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D011720:Pyrazoles; C031280:pyrazole
apoptotic effect; cytotoxicity; cytotoxicité; dérivés de la pyrazoline; effet apoptotique; human acute leukemia; leucémie aiguë humaine; molecular properties prediction; prédiction de propriétés moléculaires; pyrazoline derivatives