A Rare Natural Benzo[k,l]xanthene as a Turn-Off Fluorescent Sensor for Cu2+ Ion.

Rapid and efficient analyses of copper ions are crucial to providing key information for Cu2+ in living cells because of their biological importance. In this study, we reported one new turn-off fluorescent sensor for Cu2+ with a benzo[k,l]xanthene core, which served as an efficient cation sensor for copper ion over a wide range of other cations (Na+, K+, Ag+, Hg2+, Cd2+, Co2+, Ni2+, Zn2+, Mg2+, and Fe3+) owing to the catechol group in the aromatic core. The sensor showed selectivity for Cu2+ over other ions; the logKß for Cu2+ binding to compound 1 had a value of 13.265. In the presence of Cu2+, sensor 1 provided significant fluorescence decrement; Co2+, and Ni2+ caused a fluorescence decrement when employed at a higher concentration than Cu2+, while Na+, K+, Hg2+, Cd2+, Zn2+, and Mg2+ metal ions produced only minor changes in fluorescence intensity. Fluorescence experiments demonstrate that compound 1 may have an application as a fluorescent probe for detecting Cu2+ with a limit of detection of 0.574 µM.

Chemoenzymatic Synthesis and α-Glucosidase Inhibitory Activity of Dimeric Neolignans Inspired by Magnolol.

A chemoenzymatic synthesis of a small library of dimeric neolignans inspired by magnolol (1) is reported. The 2-iodoxybenzoic acid (IBX)-mediated regioselective ortho-hydroxylation of magnolol is described, affording the bisphenols 6 and 7. Further magnolol analogues (12, 13, 15-17, 19-23) were obtained from eugenol (3), tyrosol (4), and homovanillic alcohol (5), through horseradish peroxidase (HRP)-mediated oxidative coupling and regioselective ortho-hydroxylation or ortho-demethylation in the presence of IBX, followed by reductive treatment with Na2S2O4. A chemoselective protection/deprotection of the alcoholic group of 4 and 5 was carried out by lipase-mediated acetylation/deacetylation. The dimeric neolignans, together with 1 and honokiol (2), were evaluated as inhibitors of yeast α-glucosidase, in view of their possible utilization and optimization as antidiabetic drugs. The synthetic analogues of magnolol showed a strong inhibitory activity with IC50 values in the range 0.15-4.1 µM, much lower than those of honokiol and the reference compounds quercetin and acarbose. In particular, a very potent inhibitory activity, with an IC50 of 0.15 µM, was observed for 1,1'-dityrosol-8,8'-diacetate (15), and comparable inhibitory activities were also shown by bisphenols 6 (0.49 µM), 13 (0.50 µM), and 22 (0.86 µM). A kinetic study showed that 15 acts as a competitive inhibitor, with a Ki value of 0.86 µM.

α-Glucosidase inhibition and antioxidant activity of an oenological commercial tannin. Extraction, fractionation and analysis by HPLC/ESI-MS/MS and (1)H NMR.

Two batches of the oenological tannin Tan'Activ R, (toasted oak wood - Quercus robur), were extracted with ethanol. A fractionation on XAD-16 afforded four fractions for each extract. Extracts and fractions were evaluated for antioxidant activity (DPPH), polyphenol content (GAE) and yeast α-glucosidase inhibitory activity. Comparable results were obtained for both columns, fractions X1B and X2B showing the highest antioxidant activity. Fractions X1C and X2C notably inhibited α-glucosidase, with IC50=9.89 and 8.05µg/mL, respectively. Fractions were subjected to HPLC/ESI-MS/MS and (1)H NMR analysis. The main phenolic constituents of both X1B and X2B were a monogalloylglucose isomer (1), a HHDP-glucose isomer (2), castalin (3) gallic acid (4), vescalagin (5), and grandinin (or its isomer roburin E, 6). X1C and X2C showed a complex composition, including non-phenolic constituents. Fractionation of X2C gave a subfraction, with enhanced α-glucosidase inhibitory activity (IC50=6.15µg/mL), with castalagin (7) as the main constituent.

Dihydrobenzofuran Neolignanamides: Laccase-Mediated Biomimetic Synthesis and Antiproliferative Activity.

The biomimetic synthesis of a small library of dihydrobenzofuran neolignanamides (the natural trans-grossamide (4) and the related compounds 21-28) has been carried out through an eco-friendly oxidative coupling reaction mediated by Trametes versicolor laccase. These products, after complete spectroscopic characterization, were evaluated for their antiproliferative activity against Caco-2 (colon carcinoma), MCF-7 (mammary adenocarcinoma), and PC-3 (prostate cancer) human cells, using an MTT bioassay. The racemic neolignamides (±)-21 and (±)-27, in being the most lipophilic in the series, were potently active, with GI50 values comparable to or even lower than that of the positive control 5-FU. The racemates were resolved through chiral HPLC, and the pure enantiomers were subjected to ECD measurements to establish their absolute configurations at C-2 and C-3. All enantiomers showed potent antiproliferative activity, with, in particular, a GI50 value of 1.1 µM obtained for (2R,3R)-21. The effect of (±)-21 on the Caco-2 cell cycle was evaluated by flow cytometry, and it was demonstrated that (±)-21 exerts its antiproliferative activity by inducing cell cycle arrest and apoptosis.

2,3-Dihydrobenzofuran privileged structures as new bioinspired lead compounds for the design of mPGES-1 inhibitors.

2,3-Dihydrobenzofurans are proposed as privileged structures and used as chemical platform to design small compound libraries. By combining molecular docking calculations and experimental verification of biochemical interference, we selected some potential inhibitors of microsomal prostaglandin E2 synthase (mPGES)-1. Starting from low affinity natural product 1, by our combined approach we identified the compounds 19 and 20 with biological activity in the low micromolar range. Our data suggest that the 2,3-dihydrobenzofuran derivatives might be suitable bioinspired lead compounds for development of new generation mPGES-1 inhibitors with increased affinity.

Resveratrol-Related Polymethoxystilbene Glycosides: Synthesis, Antiproliferative Activity, and Glycosidase Inhibition.

A small library of polymethoxystilbene glycosides (20-25) related to the natural polyphenol resveratrol have been synthesized and subjected, together with their aglycones 17-19, to an antiproliferative activity bioassay toward Caco-2 and SH-SY5Y cancer cells. Six of the compounds exhibit antiproliferative activity against at least one cell line. In particular, compounds 17 and 18 proved highly active on at least one of the two cell cultures. Compound 18 showed a GI50 value of 3 µM against Caco-2 cells, a value comparable to that of the anticancer drug 5-fluorouracil. The closely related compound 19 proved inactive, and its conjugates 22 and 25 showed weak cell growth inhibition. The results indicate that minimal differences in the structure of both polymethoxystilbenes and their glycosides can substantially affect the antiproliferative activity. The possible hydrolytic release of the aglycones 17-19 by ß-glucosidase or ß-galactosidase was also evaluated. Compounds 20-25 were also tested as potential ß-glucosidase, ß-galactosidase, and α-glucosidase inhibitors. A promising inhibitory activity toward α-glucosidase was observed for 21 (IC50 = 78 µM) and 25 (IC50 = 70 µM), which might be indicative of their potential as lead compounds for development of antidiabetic or antiobesity agents.

Anti-tumor properties of cis-resveratrol methylated analogs in metastatic mouse melanoma cells.

Resveratrol (E-3,5,4'-trihydroxystilbene) is a polyphenol found in red wine that has been shown to have multiple anti-cancer properties. Although cis-(Z)- and trans-(E)-isomers of resveratrol occur in nature, the cis form is not biologically active. However, methylation at key positions of the cis form results in more potent anti-cancer properties. This study determined that synthetic cis-polymethoxystilbenes (methylated analogs of cis-resveratrol) inhibited cancer-related phenotypes of metastatic B16 F10 and non-metastatic B16 F1 mouse melanoma cells. In contrast with cis- or trans-resveratrol and trans-polymethoxystilbene which were ineffective at 10 µM, cis-polymethoxystilbenes inhibited motility and proliferation of melanoma cells with low micromolar specificity (IC50 < 10 µM). Inhibitory effects by cis-polymethoxystilbenes were significantly stronger with B16 F10 cells and were accompanied by decreased expression of ß-tubulin and pleckstrin homology domain-interacting protein, a marker of metastatic B16 cells. Thus, cis-polymethoxystilbenes have potential as chemotherapeutic agents for metastatic melanoma.

Quantification of the resveratrol analogs trans-2,3-dimethoxy-stilbene and trans-3,4-dimethoxystilbene in rat plasma: application to pre-clinical pharmacokinetic studies.

trans-2,3-Dimethoxystilbene (2,3-DMS) and trans-3,4-dimethoxystilbene (3,4-DMS) are two synthetic resveratrol (trans-3,5,4'-trihydroxystilbene) analogs. In this study, a simple HPLC method was developed and validated to determine 2,3-DMS and 3,4-DMS in rat plasma. Chromatographic separation was obtained with a reversed-phase HPLC column through a 12.5-min gradient delivery of a mixture of acetonitrile and water at the flow rate of 1.5 mL/min at 50 °C. The lower limit of quantification was 10 ng/mL. After successful validation, the pharmacokinetic profiles of 2,3-DMS and 3,4-DMS were subsequently studied in Sprague-Dawley rats. Upon single intravenous administration (4 mg/kg), 2,3-DMS had a medium volume of distribution of the central compartment (Vc = 2.71 ± 0.51 L/kg), quite rapid clearance (Cl = 52.0 ± 7.0 mL/min/kg), moderate mean transit time (MTT0→last = 131.0 ± 4.5 min) but a fairly long terminal elimination half-life (t1/2 λZ = 288.9 ± 92.9 min). Interestingly, 3,4-DMS displayed a pharmacokinetic profile apparently distinct from 2,3-DMS and it had more extensive distribution (Vc = 5.58 ± 1.73 L/kg), faster clearance (Cl = 143.4 ± 40.5 mL/min/kg) and shorter residence (MTT0→last = 61.4 ± 27.1 min). Following single oral administration (10 mg/kg), 2,3-DMS had low and erratic plasma exposure (Cmax = 37.5 ± 23.7 ng/mL) and poor oral bioavailability (2.22% ± 2.13%) while the oral bioavailability of 3,4-DMS was even poorer than 2,3-DMS. Clearly, the location of the methoxy groups had a significant impact on the pharmacokinetics of resveratrol analogs. This study provided useful information for the design of resveratrol derivatives in future study.

Effects of a ferulate-derived dihydrobenzofuran neolignan on angiogenesis, steroidogenesis, and redox status in a swine cell model.

In the ongoing search for new therapeutic compounds, lignans and neolignans, which are widely distributed in plants, deserve special attention because of their interactions with several biological targets. Searching for potential antiangiogenic agents related to natural lignans/neolignans, we were attracted by a previously studied synthetic dihydrobenzofuran neolignan. We synthesized the compound by means of an eco-friendly, enzyme-mediated biomimetic coupling of the methyl ester of ferulic acid, and the present study was aimed to deeply investigate its effect in angiogenesis bioassays validated in our laboratory. In addition, a previously well-defined granulosa cell model was employed to evaluate the effect of dihydrobenzofuran neolignan on cell viability, steroidogenesis, and redox status. Present data support the antiangiogenic effect of this neolignan. Moreover, we demonstrate that, at least at the highest concentrations tested, dihydrobenzofuran neolignan affects granulosa cell viability and steroidogenesis. In addition, the compound inhibits generation of free radicals and stimulates scavenger enzyme activities. The present data, which are a further deepening of the evaluation of the biological activities of the dihydrobenzofuran lignan in well-defined cell models, are of interest and worthy of special attention.

Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs.

BACKGROUND: Resveratrol (RSV) and resveratrol analogs have a potential use in prostate cancer chemoprevention due to effects on for example, cell growth, apoptosis, angiogenesis, and metastasis. However, inhibition of CYP17A1, a key enzyme in the androgen biosynthesis and a target for prostate cancer therapy, has not been explored as a possible mechanism behind the effects on prostate cancer. METHODS: Human adrenocortical carcinoma cells, H295R, were treated with RSV, piceatannol (PIC), 3,5,4'-triacetylresveratrol (RSVTA), 3,5-diacetylresveratrol (RSVDA), and 3,5,4'-trimethylresveratrol (RSVTM) for 24 hr at concentrations of 1, 5, 10, 25, and 50 µM. Steroid secretion, enzyme activities, and gene expression of key steps in steroidogenesis were investigated. RESULTS: Secretion of dihydroepiandrosterone (DHEA), testosterone, and cortisol were drastically decreased by all test compounds at concentrations that did not affect cell viability. Progesterone and aldosterone secretion were increased. This steroid secretion pattern can be explained by the demonstrated inhibition of CYP17A1 enzyme activity. The most efficient CYP17A1 inhibitors were the synthetic analogs RSVTA, RSVDA, and RSVTM. Inhibition by RSVTM was more selective on the 17,20-lyase activity than hydroxylase activity of CYP17A1. Treatment of cells with all compounds, except RSVTM, caused increased estradiol levels, which could be explained by the demonstrated inhibition of estrogen sulfate conjugation, catalyzed by SULT1E1. CONCLUSIONS: Our results on CYP17A1 inhibition of RSV and RSV analogs suggest a novel mechanism for chemoprevention of prostate cancer by resveratrol and the analogs. Especially RSVTM, which has a preferential inhibition on the 17,20-lyase activity of CYP17A1, may be a promising candidate for prostate cancer chemoprevention.

Bio-inspired benzo[k,l]xanthene lignans: synthesis, DNA-interaction and antiproliferative properties.

In this work twelve benzo[k,l]xanthene lignans were synthesized by biomimetic, Mn-mediated oxidative coupling of caffeic esters and amides. These compounds, bearing different flexible pendants at position C1/C2 of the aromatic core, interact with DNA in a dual mode, as confirmed by DF-STD NMR analysis and molecular docking: the planar core acts as a base pair intercalant, whereas the flexible pendants act as minor groove binders. Their antiproliferative activity was evaluated on a panel of six tumor cell lines: HT-29, Caco-2, HCT-116 (human colon carcinoma), H226, A549 (human lung carcinoma), and SH-SY5Y (human neuroblastoma). All compounds under study, except 29, resulted in activity against one or more cell lines, and the markedly lipophilic esters 13 and 28 showed the highest activity. Compound 13 was more active than the anticancer drug 5-fluorouracil (5-FU) towards HCT-116 (colon, GI50 = 3.16 µM) and H226 (lung, GI50 = 4.33 µM) cell lines.

Phenethyl caffeate benzoxanthene lignan is a derivative of caffeic acid phenethyl ester that induces bystander autophagy in WiDr cells.

We recently reported that Phenethyl caffeate benzoxanthene lignan (PCBL), a semisynthetic compound derived from Caffeic Acid Phenethyl Ester (CAPE), induces DNA damage and apoptosis in tumor cells. In this study, we further investigated whether PCBL induces autophagy in WiDr cells. We also analyzed the pathways regulating autophagy and the role of autophagy in PCBL-induced cell death. Our acridine orange staining and LC3 II expression results suggest that PCBL induces autophagosomes in WiDr cells. The levels of LC3 II expression we observed after co-treatment of PCBL with bafilomycin A1 and the reductions in p62 expression we observed after PCBL treatment in WiDr cells demonstrate increased autophagic flux, a reliable indicator of autophagic induction. The increased Beclin 1 expression in PCBL-treated cells and the incapacity of PCBL to induce LC3 II in 3-methyladenine (3-MA)-treated cells we observed suggests that PCBL-induced autophagy is class III PI3-kinase dependent. PCBL did not alter phosphorylation of the mTOR substrate p70 S6 kinase, indicating that PCBL-induced autophagy was not mTOR regulated. Two autophagy related proteins, Atg5 and Atg12, also remained uninduced during PCBL treatment. The increased caspase activity and expression levels of LC3 II and p62 we observed in response to PCBL treatment in primary glioma cells demonstrates that PCBL-induced apoptosis and autophagy were not cell line specific. Pharmacological inhibition of autophagy did not alter the antitumor efficacy of PCBL in WiDr cells. This attests to the bystander nature of PCBL-induced autophagy (in terms of cell death). In toto, these data suggest that PCBL induces a class III kinase dependent, but mTOR independent, bystander mode of autophagy in WiDr cells.

Effect of resveratrol-related stilbenoids on biomembrane models.

The interactions of the two resveratrol analogues 2-hydroxy-3,5,3',5'-tetramethoxystilbene (4) and 2-hydroxy-3,5,3',4'-tetramethoxystilbene (5) with model biomembranes were studied. The aim of this investigation was to highlight possible differences in the interactions with such biomembranes related to the minimal structural differences between these isomeric stilbenoids. In particular, different experiments on stilbenoid/biomembrane model systems using both differential scanning calorimetry (DSC) and Langmuir-Blodgett techniques were carried out to evaluate stilbenoid/multilamellar vesicle and stilbenoid/phospholipid monolayer interactions, respectively. Dimyristoylphosphatidylcholine was used as constituent of the biomembrane models and permitted the experiments to be carried out at 37 °C, close to body temperature. Kinetic studies were also run by DSC to evaluate the uptake of the resveratrol derivatives by the biomembrane model in an aqueous medium and when transported by a lipophilic carrier. The results indicated that both of the resveratrol analogues influenced the behavior of multilamellar vesicles and monolayers, biomembrane models, with 4 producing a larger effect than 5. These results are useful for better understanding the mechanism of action of these compounds. Moreover, the kinetic results could be of importance for future design of lipophilic delivery systems for these stilbenoids.

Reaction of benzoxanthene lignans with peroxyl radicals in polar and non-polar media: cooperative behaviour of OH groups.

Benzo[kl]xanthene lignans, promising bioactive polyphenols obtained by biomimetic oxidative coupling of caffeic acid derivatives, react efficiently with peroxyl radicals in both polar and non-polar solvents, thanks to the simultaneous presence of guaiacol-like and catechol-like OH-groups.

Natural-derived polyphenols as potential anticancer agents.

In this short review we report selected examples from recent literature to show the potential of natural-derived, low molecular weight polyphenols as antitumor agents. The two major groups of polyphenol analogues have been reviewed here, namely flavonoids and stilbenoids. Notwithstanding these limitations, we listed 75 compounds, many of them representing only the most potent member in a library. In addition, many studies afforded useful SARs which may be the basis for future optimization. In this regard, it is worth highlighting the close structural relationships connecting some families of tubulin inhibitors, namely analogues of chalcones, combretastatin A-4, and resveratrol. Some interesting hybrid molecules have already been obtained, such as chalcone-combretastatin and chalcone-resveratrol hybrids. The optimization of natural polyphenols reputed to be anticarcinogenic has also been addressed to improve their metabolic stability and a number of analogues, which are more stable to metabolic conversion and display comparable or higher antitumor activity than the parent compound, have been obtained. In some cases analogues with higher lipophilicity showed higher activity than the parent compound, in particular stilbenoids, flavanols, and flavone derivatives. Table 1 summarizes the main biological data on the natural-derived polyphenols cited within this review. As a whole, this survey of recently reported, natural-derived polyphenols, though not exhaustive, clearly indicates that intensive research is being carried out in the area of antitumor polyphenol analogues and suggests that in the near future some polyphenolic leads may become useful anticancer drugs or adjuvants in cancer therapy.

Antiangiogenic properties of an unusual benzo[k,l]xanthene lignan derived from CAPE (caffeic acid phenethyl ester).

Angiogenesis is normally a highly regulated process that occurs during development, reproduction, and wound repair. However, angiogenesis can also become a fundamental pathogenic process in cancer and several other diseases. To date, the synthesis of angiogenesis inhibitors has been researched in several ways also starting from bioactive plant compounds. In the present study, we tested both in an angiogenesis bioassay and in ovarian cell culture, the potential antiangiogenic effect of a natural-derived benzo[k,l]xanthene lignan (5). This unusual compound was synthesized through the biomimetic dimerization of CAPE (caffeic acid phenethyl ester), a bioactive component of honeybee propolis. The lignan showed a significant, dose-related inhibitory effect on new vessel growth in the angiogenesis bioassay and it inhibited Vascular Endothelial Growth Factor secretion in ovarian cell culture. Therefore, we indicate the natural-derived benzo[k,l]xanthene lignan 5 as a potential new angiogenesis inhibitor.

Determination of trans-2,4,3',4',5'-pentamethoxystilbene in rat plasma and its application to a pharmacokinetic study.

trans-2,4,3',4',5'-Pentamethoxystilbene (2,4,3',4',5'-PMS) is a resveratrol derivative that displayed promising pre-clinical anti-cancer activities. In this study, a simple HPLC method was developed and validated to determine 2,4,3',4',5'-PMS in rat plasma. The lower limit of quantification was 9ng/ml. The intra- and inter-day precision in terms of relative standard deviation was less than 9.7% and the bias rate ranged from -6.4 to +7.8%. The pharmacokinetics of 2,4,3',4',5'-PMS was subsequently studied in Sprague-Dawley rats. Upon intravenous administration (0.75mg/kg), 2,4,3',4',5'-PMS displayed moderate clearance (58.5±19.5ml/min/kg) and terminal elimination half-life (147±61min). Aqueous solubility appeared to be a barrier to oral absorption. When suspension was given (4mg/kg), the absolute oral bioavailability was almost nil; when 2,4,3',4',5'-PMS was fully solubilized by randomly methylated-ß-cyclodextrin, it possessed a low bioavailability (3.63±2.06%). The pharmacokinetic comparison among 2,4,3',4',5'-PMS and other methoxylated stilbenes suggested that the 2-methoxy group was unfavorable to oral bioavailability. Future investigations on 2,4,3',4',5'-PMS should be focused on chemo-prevention of colorectal carcinogenesis.

Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein.

The ABCG2 multidrug transporter is known to confer cancer cell multidrug resistance by causing the efflux of anticancer drugs; therefore, selective inhibitors have the potential to improve chemotherapeutic treatments. Here, various methoxy derivatives of resveratrol are shown to be potent inhibitors of mitoxantrone efflux by ABCG2: among a series of 11 derivatives, compound 9 (3,5,3',4'-tetramethoxy trans-stilbene) had an IC(50) of 0.16 µM and showed a maximal inhibition of 75%, as measured by flow cytometry. It was not transported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survival experiments. Compound 9 had a very low intrinsic cytotoxicity and was able to chemosensitize the growth of resistant ABCG2-transfected HEK293 cells at submicromolar concentrations. Drug-efflux inhibition was specific for ABCG2 since very low effects were observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, which produced a complete and partly competitive but not ABCG2-specific inhibition, since ABCB1 was even more strongly inhibited. The two inhibitors also displayed different effects on the ABCG2 vanadate-sensitive ATPase activity, suggesting that they either bound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining low concentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude that methoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.

Quantification of trans-3,4,5,4'-Tetramethoxystilbene in rat plasma by HPLC: application to pharmacokinetic study.

A simple HPLC method was established to quantify trans-3,4,5,4'-tetramethoxystilbene (MR-4 or DMU-212) in rat plasma. Chromatographic separation was obtained with a reversed-phase HPLC column through an 11 min gradient delivery of a mixture of acetonitrile and water at a flow rate of 1.5 mL/min at 50 °C. The limit of quantification was 15 ng/mL. The intra- and interday precisions in terms of relative standard deviation were <9% at all concentrations. Similarly, the accuracy was good, and the bias rates ranged within ±7%. The pharmacokinetic profiles of MR-4 were subsequently assessed in rats using 2-hydroxypropyl-ß-cyclodextrin as a dosing vehicle. Upon intravenous administration, MR-4 displayed moderate clearance (46.5 ± 7.6 mL/min/kg) and terminal elimination half-life (154 ± 80 min). However, the absolute oral bioavailability of MR-4 was low (6.31 ± 3.30%). Future investigation on MR-4 as a chemotherapeutic agent should be focused on colorectal cancers.

Structural basis for the potential antitumour activity of DNA-interacting benzo[kl]xanthene lignans.

The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.