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Synthesis and Cytotoxic Activity of 2,6-Diarylidenecyclohexanones and their 6-Amino-1,3-dimethyluracil Monoadducts

[ Vol. 15 , Issue. 10 ]

Author(s):

Erika Madeleyne Ramos-Rivera, Cuauhtemoc Alvarado, Jose D. Solano, Luis Roa de la Fuente, Angeles Dominguez-Rivera, Miguel Angel Vilchis-Reyes* and Miguel Angel Martinez-Urbina*   Pages 1116 - 1122 ( 7 )

Abstract:


Purpose: The aim of this study was to synthesize a series of symmetrical 2,6- diarylidenecyclohexanones (1-6) and their 6-amino-1,3-dimethyluracil monoadducts (7-10) to evaluate their cytotoxicity in a panel of cell lines. Secondly, to evaluate the effect of the most potent compound on the cell cycle of HeLa cells.

Methods: The 2,6-diarylidenecyclohexanones (1-6) were synthesized by the Claisen-Schmidt condensation using cyclohexanone and the corresponding aromatic aldehyde. Monoadducts (7-10) were obtained relying in a one-pot procedure, involving a 1,4-addition of 6-amino-1,3-dimethyluracil followed by self-condensation. The cytotoxicity assay was performed using the MTT assay. The IC50 value was obtained from the dose-response curve at 48 h of treatment. HeLa cell cycle analysis was performed by flow cytometry using propidium iodide to quantify the DNA content.

Results: Four of the synthesized 2,6-diarylidenecyclohexanones displayed moderate cytotoxicity in HeLa, K562, MCF7, SW480 and C33 human cell lines ranging from 15.5 to 63.2 µM. Compound 5 was the most potent in K562 (IC50 15.5 µM), C-33 (IC50 16.6 µM) and HeLa (19.0 µM) cell lines. In contrast, when a 6-amino-1,3-dimethyluracil group was added to the 2,6-diarylidenecyclohexanones, the activity was lost. In addition, we showed that compound 5 produces disruption in the cell cycle of HeLa cells, producing an increment in both the sub-G0/G1 and the G0/G1 phase population with a concomitant decrease in the S phase.

Conclusion: Compound 1-3 and 5, which are 2,6-diarylidenecyclohexanone derivatives, are cytotoxic on human cell lines. The formation of monoadducts of 6-amine-1,3-dimethyluracil (7-10) was detrimental for the cytotoxic potency. The appearance of a Sub G0/G1 cell population peak, on HeLa cells treated with compound 5, suggests this compound possibly induces an apoptotic cell death.

Keywords:

Chalcone, cytotoxicity, cell cycle, pyrimidine derivatives, apoptosis, HeLa cells.

Affiliation:

Division Academica de Ciencias Basicas, Universidad Juarez Autonoma de Tabasco, Cunduacan, Tabasco, 86690, Division Academica de Ciencias Basicas, Universidad Juarez Autonoma de Tabasco, Cunduacan, Tabasco, 86690, Departamento de Biologia, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico 04510, Division Academica de Ciencias Basicas, Universidad Juarez Autonoma de Tabasco, Cunduacan, Tabasco, 86690, Centro de Investigacion en Biotecnologia Aplicada (CIBA), IPN, Tlaxcala, Tlaxcala 72197, Division Academica de Ciencias Basicas, Universidad Juarez Autonoma de Tabasco, Cunduacan, Tabasco, 86690, Instituto de Quimica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Mexico 04510, D. F

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