Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells

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.

2-Phenylnaphthalene Derivatives Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Mediators by Downregulating of MAPK/NF-κB Pathways in RAW 264.7 Macrophage Cells

“…A tri-hydroxy-2-phenylnaphthalene ( PNAP - 6 ) was previously shown to exhibit significant anticancer activity in MCF-7 cells [20]. Inflammation is closely linked to cancer [22].…”

“…Many anti-inflammatory clinical drugs such as propranolol, naphazoline, and nabumetone possess the bicyclic naphthalene skeleton [19]. Recently, we reported that PNAP - 6 exhibits potent anti-cancer activity [20]. However, it was unclear whether the MAPK and NF-κB pathways were activated in PNAP-mediated anti-inflammation.…”

<p>6,7-Dihydroxy-2-(4′-hydroxyphenyl)naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway</p>

“…In the past few years, a series of PNAP derivatives have been synthesized in our laboratory and we have assessed their effects on breast cancer and macrophage cells. Our research has shown that 6,7-dihydroxy-2-(4′-hydroxyphenyl)naphthalene (PNAP-6) exhibits potent anti-breast cancer activity, inducing cell cycle arrest and death of breast cancer cells 2. Moreover, PNAP-6 reduces the production of lipopolysaccharide-induced pro-inflammatory mediators, such as IL-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and COX-II 4.…”

“…Therefore, it is imperative to develop drugs that are more effective than those currently in use. The spatial and conformational requirements of 2-phenylnaphthalenes (PNAPs) and genistein are pharmacologically similar 2. Genistein is well known as an anticancer agent.…”

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

“…After analysing the binding modes of known MDM2 inhibitors and CDK4 inhibitors, we speculated that fusion of the planar tetrahydronaphthalene (THN) ring at the C3-position of oxindole might generate a scaffold that could bind at the P53-binding site in MDM2 as well as at the allosteric site in CDK4. We started with THN 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 and spirooxindole derivatives 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 because they are privileged drug-like architectures, so the resulting THN-fused C3-spirooxindoles should possess good druglikeness ( Fig. 2 C).…”