Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation

Journal of Experimental & Clinical Cancer Research

Rosanna Filosa¹  Michele Caraglia²  Mario De Rosa²  Annalisa La Gatta²  Giovanni Capranico³  Anna Capasso¹  Antonio Massa⁴  Jessica Marinello³  Maria Castellano²  Antonella Peduto¹  Michela Festa¹  Carmen Petronzi¹ 

[1]Department of Pharmaceutical and Biomedical Sciences, University of Salerno, via Ponte Don Melillo, Fisciano, SA, 84084, Italy

[2]Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via Costantinopoli 16, Naples, 80138, Italy

[3]Department of Biochemistry G. Moruzzi, University of Bologna, via Irnerio 48, Bologna, 40126, Italy

[4]Department of Chemistry, University of Salerno, via Ponte Don Melillo, Fisciano, SA, 84084, Italy

关键词: Reactive oxygen species;    PARP;    Melanoma cell line M14;    Benzoquinones;    Cytotoxicity;    Apoptosis;   

Others  :  825172
DOI  :  10.1186/1756-9966-32-24

 received in 2013-02-21, accepted in 2013-04-12,  发布年份 2013

【 摘 要 】

Background

Tumors are diseases characterized by uncontrolled cell growth and, in spite of the progress of medicine over the years, continue to represent a major threat to the health, requiring new therapies. Several synthetic compounds, such as those derived from natural sources, have been identified as anticancer drugs; among these compounds quinone represent the second largest class of anticancer agents in use. Several studies have shown that these act on tumor cells through several mechanisms. An important objective of this work is to develop quinoidscompounds showing antitumor activity, but with fewer side effects. The parachinone cannabinol HU-331, is a small molecule that with its core 4-hydroxy-1,4-benzoquinone, exhibits a potent and selective cytotoxic activity on different tumor cell lines. A series of derivatives 3-hydroxy-1,4-benzochinoni were thus developed through HU-331 chemical modifications. The purpose of the work is to test the ability of the compounds to induce proliferative inhibition and study the mechanisms of cell death.

Methods

The antitumor activities were evaluated in vitro by examining their cytotoxic effects against different human cancer cell lines. All cell lines tested were plated in 96-multiwell and treated with HU-100-V at different concentrations and cell viability was evaluated byMTT assay. Subsequently via flow cytometry (FACS) it was possible to assess apoptosis by the system of double labeling with PI and Annexin-V, and the effect of the compounds on ROS formation by measuring the dichlorofluorescein fluorescence.

Results

The substitution by n-hexyl chain considerably enhanced the bioactivity of the compounds. In details, 2-hexyl-5-hydroxycyclohexa-2,5-diene-1,4-dione (V), 2,5-Dimethoxy-3-hexyl-2,5-cyclohexadiene-1,4-dione (XII) and 2-hydroxy-5-methoxy-3-hexyl-cyclohexa-2,5-diene-1,4-dione (XIII) showed most prominent cytotoxicity against almost human tumour cell lines. Compound V was further subjected to downstream apoptotic analysis, demostrating a time-dependent pro-apoptotic activity on human melanoma M14 cell line mediated by caspases activation and poly-(ADP-ribose)-polymerase (PARP) protein cleavage.

Conclusions

These findings indicate that 2-hexyl-5-idrossicicloesa-2,5-diene-1,4-dione can be a promising compound for the design of a new class of antineoplastic derivatives.

Carmen Petronzi, Michela Festa, Antonella Peduto and Maria Castellano: equally contributed equally to this work.

【 授权许可】

   
2013 Petronzi et al.; licensee BioMed Central Ltd.

【 图 表 】

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