Chalcogen-containing phenolics as antiproliferative agents.

AIM: The increasing number of cancer cases has stimulated researchers to seek for novel approaches. We have combined two bioactive moieties: a polyphenolic scaffold and an organoselenium motif. Four different families (isothiocyanates/thioureas, and their selenium isosters) derived from dopamine, (±)-norepinephrine and R-epinephrine were accessed. RESULTS: Heterocumulenes derived from dopamine and ß-O-methylnoradrenaline were strong antiproliferative agents (GI50<10 µM). Selenoureas derived from ß-O-methylnoradrenaline bearing electron-withdrawing groups (halogen, -NO2, -Ph) on the phenyl ring, were also strong antiproliferative agents, besides exhibiting good antiradical and glutathione peroxidase-like activities. Up to a 14-fold increased activity was achieved compared with classical chemotherapeutic agents, exhibiting also different mechanisms of action (cell cycle assays). Redox analysis on HeLa cells suggested an increase of ROS levels after the incubation period. CONCLUSION: the combination of organoselenium and phenolic moieties might provide valuable lead compounds with relevant antiproliferative properties.

New selenosteroids as antiproliferative agents.

Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI50 values in the range 2.0-4.1 µM for all the tested tumor cell lines, with increased potency compared with commonly used chemotherapeutic agents, like 5-fluorouracil and cisplatin. Cell cycle analysis revealed that selenoureas induced accumulation of cells in the G1 phase of the cell cycle in the breast cancer cell lines HBL-100 and T-47D; therefore, a different mechanism than cisplatin, that induces cell cycle accumulation in the S phase as a result of DNA damage, must be involved. In the rest of the tumor cells, a slight increase of the S compartment was observed. Moreover, selenosteoids turned out to be excellent glutathione peroxidase (GPx) mimics for the catalytic removal of deleterious H2O2 (t1/2 8.0-22.5 min) and alkyl peroxides (t1/2 23.0-38.9 min) when used in substoichiometric amounts (1% molar ratio), thus providing a valuable tool for reducing the intrinsic oxidative stress in tumor progression.

Selenoureido-iminosugars: A new family of multitarget drugs.

Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of ß-glucosidase, Ki = 1.6-5.5 µM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 µM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.

Antiproliferative effect of extract from endophytic fungus Curvularia trifolii isolated from the "Veracruz Reef System" in Mexico.

CONTEXT: It is well known that marine fungi are an excellent source of biologically active secondary metabolites, and by 2011, it was reported that over 400 bioactive metabolites were derived from marine fungi. OBJECTIVE: This study establishes the basis for future research on antiproliferative compounds of marine endophytes inhabited in the Veracruz Reef System. MATERIALS AND METHODS: Isolation of the 34 fungal strains was carried out by microbiological method from samples of sponges, corals, and other biological material from the Veracruz Reef System. The fungal biomass and broth were separated and extracted with a mixture of solvents MeOH:CHCl3. Characterization and molecular identification of the fungal strains were performed through microbiological methods and the analysis of the ITS-rDNA regions. Antiproliferative activity was tested at a dose of 250 µg/mL on human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D, and WiDr by the SRB assay after 48 h-exposure to the fungal extracts. RESULTS: The extracts from five isolates showed an antiproliferative effect against one or more of the tested cell lines (percentage growth < 50%). The mycelial extract from the isolate LAEE 03 manifested the highest activity against the five cell lines (% PG of 17 HBL-100, 19 HeLa, 23 SW1573, -6 T-47D, and 10 WiDr) and the strain was identified as Curvularia trifolii (Kauffman) Boedijn (Pleosporaceae). DISCUSSION AND CONCLUSION: The results obtained indicate that the extract from a marine derived C. trifolii has the antiproliferative effect, thus suggesting that this organism is a good candidate for further analysis of its metabolites.

Influence of the configurational pattern of sp(2)-iminosugar pseudo N-, S-, O- and C-glycosides on their glycoside inhibitory and antitumor properties.

The synthesis of a complete series of cyclic carbamate-type sp(2)-iminosugar N-, S-, O- and C-octyl pseudoglycosides related to nojirimycin, mannojirimycin and galactonojirimycin, all having the α-pseudoanomeric configuration, is reported. The gem-diamine-type N-pseudoglycosides can be accessed directly from the corresponding reducing sp(2)-imisosugar precursors by reaction with octylamine in methanol, whereas per-O-acetyl or 1-fluoro derivatives were used as pseudoglycosyl donors for the preparation of S-pseudoglycosides or O- and C-pseudoglycosides, respectively. Evaluation of their inhibitory properties against a panel of glycosidases evidenced selectivity profiles that strongly depend on the configurational pattern and the nature of the glycosidic linkage. On the contrary, the antiproliferative activity determined against a panel of tumor cell lines was largely independent of the relative orientation of the hydroxyl groups in the sp(2)-iminosugar moiety. Indeed, sp(2)-iminosugar representatives exhibiting significant growth inhibition potencies were identified in all three configurationally different types of compounds studied, namely α-d-gluco, α-d-manno and α-d-galacto glycoside analogs. Interestingly, none of the compounds affected viability and mortality of normal cells at the used concentrations. Altogether, the results strongly suggest that the anticancer activity of amphiphilic sp(2)-iminosugar glycosides might be unrelated, or not solely related, to their glycosidase inhibitory activity.

Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-epi-Luffarin I and Luffarin A.

Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from 2.8-15µM, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure-activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with [Formula: see text] values in the range 2.8-15 M.

Synthesis and bioactivity of Luffarin I.

The first synthesis of Luffarin I, sesterterpenolide isolated from sponge Luffariella geometrica, has been accomplished from commercially available sclareol. The key strategy involved in this synthesis is the diastereoselective reduction of an intermediate ketone. Luffarin I against human solid tumor cell lines showed antiproliferative activities (GI50) in the range 12-17 µM.

Phenolic thio- and selenosemicarbazones as multi-target drugs.

A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon their in vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 µM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 µM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 µM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 µM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 µM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin.