Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells.
Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.
Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland.
Angelika
A
Długosz
Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland.
Katarzyna
K
Gach
Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Łódź, Poland.
Jacek
J
Szymański
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland.
Jakub
J
Modranka
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland.
Tomasz
T
Janecki
Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland.
Anna
A
Janecka
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004249:DNA Damage / Q000187:drug effects; D005663:Furans; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010757:Phosphorous Acids / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005663:Furans; D007211:Indoles; D009285:Naphthoquinones; D010757:Phosphorous Acids; C570063:phosphonic acid; C030374:indole; C039281:furan
MTT test; apoptosis; flow cytometry; real-time PCR