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A small collection of C2‐symmetric hydroxylated biphenyl derivatives featuring an α,β‐unsaturated ketone as a lead structure was prepared, and the capacity of these compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve the delivery of compounds into the cell by modulation of the phenolic hydroxy protecting group. The hydroxylated biphenyl structure bearing an α,β‐unsaturated ketone and a phenolic‐O‐prenylated chain was found to facilitate the delivery of the molecule and interactions with biological targets. Four compounds showed antiproliferative activity resulting in IC50 values in the range of 1.2 to 2.8 μM.

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Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration of the hydrocarbon “tails” of the lipids. This process is known as “lipid peroxidation”, and the accumulation of the oxidation products as peroxides and the aldehydes and acids derived from them are often used as a measure of oxidative stress levels. In total, 40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breaking antioxidant activity, and thus as modulators of oxidative stress. This included natural and natural-like ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methods such as density functional theory (DFT) and quantitative structure–activity relationship ((Q)SAR) modeling) were used to clarify their structure–activity relationship. Kinetics of non-inhibited and inhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress is considered. Special attention has been paid to chemical reactions resulting in the initiation of free radicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolic ring of hydroxylated phenols and biphenols, and the concentration were discussed.

Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 μM for 11 and 2.0 ± 0.7 μM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.

Onychomycosis is a common nail infection mainly caused by species belonging to the F. oxysporum, F. solani, and F. fujikuroi species complexes. The aim of this study was to evaluate the in vitro susceptibility of six representative strains of clinically relevant Fusarium spp. toward a set of natural-occurring hydroxycinnamic acids and their derivatives with the purpose to develop naturally occurring products in order to cope with emerging resistance phenomena. By introducing a prenylated chain at one of the hydroxy groups of trans-cinnamic acids 1–3, ten prenylated derivatives (coded 4–13) were preliminarily investigated in solid Fusarium minimal medium (FMM). Minimal inhibitory concentration (MIC) and lethal dose 50 (LD50) values were then determined in liquid FMM for the most active selected antifungal p-coumaric acid 3,3′-dimethyl allyl ester 13, in comparison with the conventional fungicides terbinafine (TRB) and amphotericin B (AmB), through the quantification of the fungal growth. Significant growth inhibition was observed for prenylated derivatives 4–13, evidencing ester 13 as the most active. This compound presented MIC and LD50 values (62–250 µM and 7.8–125 µM, respectively) comparable to those determined for TRB and AmB in the majority of the tested pathogenic strains. The position and size of the prenylated chain and the presence of a free phenol OH group appear crucial for the antifungal activity. This work represents the first report on the activity of prenylated cinnamic esters and ethers against clinical Fusarium spp. and opens new avenues in the development of alternative antifungal compounds based on a drug repositioning strategy.

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Malignant melanoma (MM) is one of the most aggressive cancers that affect humans. It is the most common and fatal skin cancer, with an incidence that is critically increasing in Western populations (15 times in the last 40 years) and for which, in the advanced stages, there is no effective therapy. The search for new compounds able to control it is therefore essential. The hydroxylated biphenyl compound (3E,3′E)-4,4′-(5,5′,6,6′-tetramethoxy-[1,1′-biphenyl]-3,3′-diyl)bis(but-3-en-2-one), namely D6, a structural analogue of curcumin, showed a strong antitumor activity on MM cells both in vitro and in vivo, as we have recently described [1]. The mechanisms of action of this compound are not clear yet, but it inhibits cancer cells growth by inducing apoptosis without affecting normal fibroblasts growth. Firstly we investigated the ability of D6 to enter cells by Liquid Chromatography-Mass Spectrometry (LC-MS) analysis. The LC-MS data showed a quick cellular uptake of D6 with a maximum peak after about 2 hours. To investigate on the effects of D6 treatment on the cell cycle progression in MM cells, we performed flow cytometry analysis, which evidenced a cell cycle arrest in the G2/M phase. Gene expression profiles analysis using Illumina® high-density microarrays, was carried out on D6 treated MM cells and normal fibroblasts allowing the identification of 599 transcripts whose expression was modulated by D6 treatment in MM cells but not in normal fibroblast. The analysis of results, performed by Ingenuity Pathway Analysis software, showed the centrality of CDKN1A gene, encoding p21, a major negative cell cycle regulator, which was strongly over expressed, while cyclin B and cdc25 phosphatase, showed both to be down modulated. Other genes which expression interestingly appeared to be decreased by D6 activity were the oncogenes c-kit and PI3K, suggesting a down regulation of both c-kit mediated and PI3K/AKT signal transduction pathways driving to cell proliferation. Modulation of expression of these specific genes has been confirmed at a protein level by western blotting analysis. Moreover our results pointed out an upregulation of several heat shock family genes, which is probably due to a curcumin related anti inflammatory effect of D6. The preliminary results of these analysis show that D6 induces molecular changes in MM cells at both gene expression and protein levels, involving major cell proliferation regulatory pathways. [1] Marina Pisano et al. (2010).Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells. Molecular Cancer, 9:137. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3804. doi:1538-7445.AM2012-3804