Synthesis and Evaluation of Antileishmanial and Cytotoxic Activity of Benzothiopyrane Derivatives.

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.

An Ethnopharmacological, Phytochemical and Pharmacological Review on Lignans from Mexican Bursera spp.

The genus Bursera belongs to the family Burseraceae and has been used in traditional Mexican medicine for treating various pathophysiological disorders. The most representative phytochemicals isolated from this genus are terpenoids and lignans. Lignans are phenolic metabolites known for their antioxidant, apoptotic, anti-cancer, anti-inflammatory, anti-bacterial, anti-viral, anti-fungal, and anti-protozoal properties. Though the genus includes more than 100 species, we have attempted to summarize the biological activities of the 34 lignans isolated from selected Mexican Bursera plants.

General, Mild, and Metal-Free Synthesis of Phenyl Selenoesters from Anhydrides and Their Use in Peptide Synthesis.

A mild, practical, and simple procedure for phenyl selenoesters synthesis from several anhydrides and diphenyl diselenide was developed. This transition-metal-free method provides a straightforward entry to storable Fmoc-amino acid selenoesters which are effective chemoselective acylating reagents. An application to oligopeptide synthesis was illustrated.

Diterpenoids and Triterpenoids from the Resin of Bursera microphylla and Their Cytotoxic Activity.

A chemical study of the nonpolar fraction of a methanol-soluble extract of Bursera microphylla resin yielded a variety of di- and triterpenoids. In total, 15 compounds were isolated, of which three are new, namely, malabaricatrienone (1), malabaricatrienol (2), and microphyllanin (3). The antiproliferative activity of the major compounds was evaluated in different murine cancer cell lines (M12.C3.F6 and RAW264.7) and human cancer cells (A549, HeLa, and PC-3). The new compounds (1-3) did not show significant antiproliferative activity. The known compounds ariensin (4), burseran (5), and dihydroclusin diacetate (6) were effective against the RAW264.7 cell line, with IC50 values in the micromolar range.

Chemical Composition and Biological Activities of Fragrant Mexican Copal (Bursera spp.).

Copal is the Spanish word used to describe aromatic resins from several genera of plants. Mexican copal derives from several Bursera spp., Protium copal, some Pinus spp. (e.g., P. pseudostrobus) and a few Fabaceae spp. It has been used for centuries as incense for religious ceremonies, as a food preservative, and as a treatment for several illnesses. The aim of this review is to analyze the chemical composition and biological activity of commercial Mexican Bursera copal.

Hinokinin, an emerging bioactive lignan.

Hinokinin is a lignan isolated from several plant species that has been recently investigated in order to establish its biological activities. So far, its cytotoxicity, its anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is its notable anti-trypanosomal activity.

Magnesium bis(monoperoxyphthalate) hexahydrate as mild and efficient oxidant for the synthesis of selenones.

A new, efficient and mild method for the direct oxidation of selenides to selenones using magnesium bis(monoperoxyphthalate) hexahydrate (MMPP) has been developed. Noteworthy this transformation proceeds at room temperature, employs a cheap and safety oxidant and has a broad functional group tolerance. Moreover, the produced selenones could be useful intermediates for the synthesis of different heterocyclic compounds.

Conjugation of l-NAME to prenyloxycinnamic acids improves its inhibitory effects on nitric oxide production.

A series of 10 compounds resulting from the conjugation of O-prenylated naturally occurring benzoic and cinnamic acids to l-NAME were synthesized and tested together with the corresponding unprenylated parent molecule as anti-inflammatory agents for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages. Results indicated that the coupling between O-geranyl and O-isopentenylcinnamic acids and l-NAME led to products with an enhanced activity when compared to the parent compounds.

Inhibition of COX-1 activity and COX-2 expression by 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid and its semi-synthetic derivatives.

Oxyprenylated naturally occurring cinnamic acids displayed efficient and promising biological activities. Aim of this study was to characterize the effects of 3-(4'-geranyl-3'-methoxy)phenyl-2-trans propenoic acid and its selected semi-synthetic analogues, on COX-2 expression and activity, and on COX-1 activity, in purified systems or in whole cell systems. The anti-inflammatory activity of title compounds (1) was tested as inhibition of COX-2 on isolated monocytes stimulated with LPS (10 µg/ml). COX-2 expression was completely suppressed when monocytes were incubated with 100 µM of 3-(4'-geranyl-3'-methoxy)phenyl-2-trans propenoic acid (1) or 3-(4'-isopentenyloxy)phenyl-2-trans propenoic acid (4). Moreover compounds (1) and (4) inhibit dose-dependently LPS-induced COX-2 expression.

Growth inhibitory activities of oxyprenylated and non-prenylated naturally occurring phenylpropanoids in cancer cell lines.

A series of 25 selected oxyprenylated natural phenylpropanoids were synthesized, and their growth inhibitory activities were evaluated in vitro together with 14 other commercially available non-alkylated compounds belonging to the same chemical series. The compounds were tested on six human cancer cell lines using MTT colorimetric assays. The data reveal that of the six chemical groups (G) studied, coumarins (G1), cinnamic and benzoic acids (G2), chalcones (G3), acetophenones (G4), anthraquinones (G5), and cinnamaldehydes and cinnamyl alcohols (G6), G2-related compounds displayed the weakest growth inhibitory activities in vitro, whereas G5-related compounds displayed the highest activities. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various levels of resistance to different pro-apoptotic stimuli. These analyses revealed that compounds 20 (4,2',4'-trihydroxychalcone), and 30 and 31 (two cinnamaldehydes) were cytostatic and able to overcome the intrinsic resistance of U373 cancer cells to pro-apoptotic stimuli.

Topical anti-inflammatory activity of boropinic acid and its natural and semi-synthetic derivatives.

Boropinic acid is a natural isopentenyloxycinnamic acid extracted from the aerial parts of Boronia pinnata Sm. (Rutaceae) with soybean 5-lipoxygenase inhibitory activity. In this paper the topical anti-inflammatory activity of boropinic acid and some of its natural and semi-synthetic derivatives was evaluated using the Croton oil ear test in mice as a model of acute inflammation. Some of the tested compounds (15, 17, 19, 20) revealed an effect comparable (ID(50)=0.18÷0.72µmol/cm(2)) to that of the reference drug indomethacin (ID(50)=0.23µmol/cm(2)), a non-steroidal anti-inflammatory drug.

Antibacterial and anti-inflammatory activities of 4-hydroxycordoin: potential therapeutic benefits.

4-Hydroxycordoin (1), a natural isopentenyloxychalcone, is a plant secondary metabolite that is relatively rare. Since there are very few reports about the biological activities of 1, its potential benefits for periodontal disease were investigated. A marked and dose-dependent antibacterial activity of 1 was observed against the three major periodontal pathogens, Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia. Moreover, compound 1 showed an antiadhesion effect, since it inhibited attachment of P. gingivalis to oral epithelial cells. Finally, using a macrophage model, the ability of 1 to inhibit the secretion of inflammatory mediators induced by Aggregatibacter actinomycetemcomitans lipopolysaccharide was demonstrated. The anti-inflammatory effect observed was associated with reduced activation of the nuclear factor-κB (NF-κB) p65 and activator protein-1 (AP-1) pathways.

Protective effects of Commiphora erythraea resin constituents against cellular oxidative damage.

By bioguided fractionation of the hexane extract of Commiphora erythraea resin we isolated four furanosesquiterpenoids that were tested for their protective activity against oxidative stress. Furanodienone and 1,10(15)-furanogermacra-dien-6-ones showed to be potent inhibitors of lipid peroxidation (IC(50) of -0.087 µM), being more active than the methoxylated analogues. Furthermore, using BV2 microglial cells, we found that furanodienone from C. erythraea is able to counteract LPS-induced cell death and decrease LPS-induced NO generation thus protecting microglial cells from LPS-induced cytotoxicity. Finally, docking studies were undertaken to gain insight into the possible binding mode of the isolated compounds at 5-LOX binding site.

Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors.

Auraptene is a prenyloxycoumarin from Citrus species with chemopreventive properties against colitis-related colon and breast cancers through a yet-undefined mechanism. To decipher its mechanism of action, we used a ligand-structure based approach. We established that auraptene fits with a pharmacophore involved in both the inhibition of acyl-CoA:cholesterol acyl transferase (ACAT) and the modulation of estrogen receptors (ERs). We confirmed experimentally that auraptene inhibits ACAT and binds to ERs in a concentration-dependent manner and that it inhibited ACAT in rat liver microsomes and in intact cancer cells of murine and human origins, with an IC(50) value in the micromolar range. Auraptene bound to ERs with affinities of 7.8 µM for ERα and 7.9 µM for ERß, stabilized ERs, and modulated their transcriptional activity via an ER-dependent reporter gene and endogenous genes. We further established that these effects correlated well with the control of growth and invasiveness of tumor cells. Our data shed light on the molecular mechanism underlying the anticancer and chemopreventive effects of auraptene.

Colorectal cancer chemoprevention by 2 beta-cyclodextrin inclusion compounds of auraptene and 4'-geranyloxyferulic acid.

The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with beta-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/beta-CD or AUR/beta-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/beta-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 +/- 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/beta-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/beta-CD and AUR/beta-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-alpha, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1beta, which were induced in the adenocarcinomas. Our findings indicate that GOFA/beta-CD and AUR/beta-CD, especially GOFA/beta-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.

Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents.

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.

Chemistry and pharmacology of collinin, active principle of Zanthoxylum spp.

Collinin is a geranyloxycoumarins isolated in small amounts from plants of the Rutaceae family. Synthetic schemes were recently developed allowing to handle collinin in sufficient quantities to put in evidence valuable biological effects. The aim of this review is to examine the phytochemical and pharmacological properties of this compound.

A novel prodrug of 4'-geranyloxy-ferulic acid suppresses colitis-related colon carcinogenesis in mice.

The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

Neuroprotective effect of prenyloxycoumarins from edible vegetables.

The present study is designed to investigate the effect of some natural prenyloxyphenylpropanoids as neuroprotective agents against NMDA-induced toxicity in mixed cortical cell cultures containing both neurons and astrocytes. Excitotoxicity was induced by exposure of cultures to NMDA (100microM) at room temperature in a HEPES-buffered salt solution followed by incubation at 37 degrees C for the following 24h in MEM-Eagle's supplemented with 15.8mM NaHCO(3) and 25mM glucose. Tested compounds were mixed with NMDA. Neuronal injury was measured in all experiments by examination of cultures with phase-contrast microscopy at 20x, 18-20h after the insult while neuronal damage was quantitatively assessed by counting dead neurons stained with trypan blue and by measuring lactate dehydrogenase (LDH) released in the medium. Results showed that only natural prenyloxyphenylpropanoids containing a coumarin nucleus, namely 7-isopentenyloxycoumarin and auraptene, both found in nature from plants belonging to the genus Citrus and other of the family of Rutaceae, including edible ones, exerted a good dose-dependent manner protective effect against NMDA-induced neurotoxicity in particular at concentrations ranging from 1 to 10microM.

Effects of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid and its ester derivatives on biofilm formation by two oral pathogens, Porphyromonas gingivalis and Streptococcus mutans.

The aim of this study was to investigate the effect of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid, active principle isolated from Acronychia baueri Schott, and its ester derivatives on biofilm formation by two important oral pathogens, Porphyromonas gingivalis and Streptococcus mutans. The parent acid and conjugates with vanillic acid, 2-hydroxynaphthoquinone and guaiacol caused a significant and reproducible inhibition of P. gingivalis biofilm formation. This effect could be related to the ability of the compounds to inhibit bacterial growth. These compounds also efficiently caused a reduction of biofilm formation by S. mutans, a phenomenon not related to growth inhibition. These data suggest that 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid and some of its ester derivatives may have a therapeutic/preventive potential for oral infections.