Abstract
In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 μM against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity.
Highlights
Breast cancer is the most common cause of cancer death in females; the search for a new and effective anticancer agent is imperative
The results indicate that PNAP-3h and -6h possess enhanced and selective cytotoxicity against MCF-7 cells and show low toxicity toward MCF-10A cells
The two 2-phenylnaphthalenes PNAP-3h and -6h, which contain a hydroxyl group at the C-7 position of the naphthalene ring, exhibited better cytotoxic activities against the MCF-7 cell line. These results suggest that cytotoxicity is markedly promoted by the presence of a hydroxyl group at the C-7 position of the naphthalene ring
Summary
Breast cancer is the most common cause of cancer death in females; the search for a new and effective anticancer agent is imperative. Naphthalene derivatives display potent antiarrhythmia, anti-tumor, and antioxidant activities [1]. 2-phenylnaphthalenes (PNAPs) have similar spatial and conformational requirements to genistein (an isoflavone) and exhibit a large number of biological and biomedical effects [2]. 1-substituted naphthalene, not 2-substituted naphthalene, is obtained by the electrophilic aromatic substitution of naphthalene. To the best of our knowledge, studies on the relationship between the structure and cytotoxicity of multi-substituted PNAPs are rare. We synthesized unsubstituted PNAP-1, seven methoxy-PNAPs (PNAP-2−PNAP-8), six corresponding hydroxy-PNAPs (PNAP-2h−PNAP-7h), and one amino-PNAP (PNAP-8h) and investigated their anticancer structure-activity relationships and mechanisms of action in the MCF-7 cell line
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