Algal-Derived Halogenated Sesquiterpenes from Laurencia dendroidea as Lead Compounds in Schistosomiasis Environmental Control.

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (-)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.

Involvement of the NF-κB and PI3K/Akt/mTOR pathways in cell death triggered by stypoldione, an o-quinone isolated from the brown algae Stypopodium zonale.

Multiple myeloma (MM) is a clonal plasma cell malignancy that remains incurable to date. Thus, the aims of this study were to evaluate the involvement of the NF-κB and PI3K/Akt/mTOR pathways in the cytotoxicity of stypoldione, an o-quinone isolated from the brown algae Stypopodium zonale, in MM cells (MM1.S). The cytotoxic effect was evaluated in MM1.S cells and peripheral blood mononuclear cells (PBMCs) by MTT assay. The stypoldione reduced the cell viability of MM1.S cells in a concentration and time-dependent manner (IC50 in MM.1S from 2.55 to 5.38 µM). However, it was also cytotoxic to PBMCs, but at a lower range. Additionally, no significant hemolysis was observed even at concentration up to 10 times the IC50 . Apoptotic cell death was confirmed by cell morphology and Annexin V-FITC assay. Stypoldione induced intrinsic and extrinsic apoptosis by increasing FasR expression and reactive oxygen species (ROS) production, inverting the Bax/Bcl-2 ratio, and inducing ΔΨm loss, which resulted in AIF release and caspase-3 activation. It also increased Ki-67 and survivin expression and inhibited the NF-κB and PI3K/Akt/mTOR pathways. These results suggest that stypoldione is a good candidate for the development of new drugs for MM treatment.

Algal-derived halogenated Sesquiterpenes from Laurencia dendroidea as lead compounds in Schistosomiasis environmental control

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (−)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.

Cytotoxic mechanisms of primin, a natural quinone isolated from Eugenia hiemalis, on hematological cancer cell lines.

Considering the high morbidity and mortality rates associated with hematological malignancies and the frequent development of drug resistance by these diseases, the search for new cytotoxic agents is an urgent necessity. The new compounds should present higher efficiency and specificity in inducing tumor cell death, be easily administered and have little or negligible adverse effects. Quinones have been reported in the literature by their several pharmacological properties, including antitumor activity, thus, the aim of this study was to investigate the cytotoxic effect of primin, a natural quinone, on hematological malignancies cell lines. Primin was highly cytotoxic against the three cell lines included in this study (K562, Jurkat and MM.1S) in a concentration- and time-dependent manner, as demonstrated by the MTT method. The compound triggered an apoptotic-like cell death, as observed by ethidium bromide/acridine orange staining, DNA fragmentation and phosphatidylserine exposure after labeling with Annexin V. Both intrinsic and extrinsic apoptosis are involved in cell death induced by primin, as well as the modulation of cell proliferation marker KI-67. The activation of intrinsic apoptosis appears to be related to a decreased Bcl-2 expression and increased Bax expression. While the increase in FasR expression signals activate extrinsic apoptosis. The results suggest that primin is a promising natural molecule that could be used in hematological malignancies therapy or as prototypes for the development of new chemotherapics.

Apoptotic events induced by a natural plastoquinone from the marine alga Desmarestia menziesii in lymphoid neoplasms.

There exists an urgent need for the development of new drugs for the treatment of lymphoid neoplasms. The aim of this study was to evaluate the cytotoxic effect of the marine plastoquinone 9'-hydroxysargaquinone (9'-HSQ), focusing on investigation of the mechanism by which it causes death in lymphoid neoplastic cells. This particular plastoquinone reduced the cell viability of different hematological tumor cell lines in a time-dependent and concentration-dependent manner. Intrinsic apoptosis occurred with time-dependent reduction of mitochondrial membrane potential (42.3 ± 1.1% of Daudi cells and 18.6 ± 5.6% of Jurkat cells maintained mitochondrial membrane integrity) and apoptosis-inducing factor release (Daudi: 133.3 ± 8.1%, Jurkat: 125.7 ± 6.9%). Extrinsic apoptosis also occurred, as reflected by increased FasR expression (Daudi: 139.5 ± 7.1%, Jurkat: 126.0 ± 1.0%). Decreases were observed in the expression of Ki-67 proliferation marker (Daudi: 67.5 ± 2.5%, Jurkat: 84.3 ± 3.8%), survivin (Daudi: 66.0 ± 9.9%, Jurkat: 63.1 ± 6.0%), and NF-κB (0.7 ± 0.04% in Jurkat cells). Finally, 9'-HSQ was cytotoxic to neoplastic cells from patients with different lymphoid neoplasms (IC50: 4.9 ± 0.6 to 34.2 ± 0.4 µmol/L). These results provide new information on the apoptotic mechanisms of 9'-HSQ and suggest that it might be a promising alternative for the treatment of lymphoid neoplasms.

MICONIDINE acetate, a new selective and cytotoxic compound with synergic potential, induces cell cycle arrest and apoptosis in leukemia cells.

Plants are important sources of biologically active compounds and they provide unlimited opportunities for the discovery and development of new drug leads, including new chemotherapeutics. Miconidin acetate (MA) is a hydroquinone derivative isolated from E. hiemalis. In this study we demonstrated that MA was cytotoxic against acute leukemia (AL), solid tumor cells and cancer stem cells, with the strongest effect exhibited against AL. Furthermore, it was non-cytotoxic against non-tumor cells and did not cause significant hemolysis. MA blocks the G2/M phase and causes cytostatic effects, acting in a similar way to dexamethasone by increasing PML expression. The compound also triggered intrinsic and extrinsic apoptosis by modulating Bax, FasR and survivin expression. This led to an extensive mitochondrial damage that resulted in AIF, cytochrome c and endonuclease G release, caspase-3 and PARP cleavage and DNA fragmentation. We have further demonstrated that MA was strongly cytotoxic against neoplastic cells collected from patients with different AL subtypes. Interestingly, MA increased the cytotoxic effect of chemotherapeutics cytarabine and vincristine. This study indicates that MA may be a new agent for AL and highlights its potential as a new source of anticancer drugs. Graphical abstract MA blocks G2/M phase with PML expression and KI67 inhibition, ROS generation and intrinsic and extrinsic apoptosis, leading to mitochondrial damage, caspase 3 and PARP cleavage and DNA fragmentation.

An overview of odoriferous marine seaweeds of the Dictyopteris genus: insights into their chemical diversity, biological potential and ecological roles

ABSTRACT Since the middle of the twentieth century the marine algae have attracted attention as a source of new drugs. Dictyopteris is an important group of marine seaweeds and is widely distributed in tropical, subtropical and temperate regions. This genus is known by its characteristic "ocean smell". Some species show a distinct phytochemistry, with specific secondary metabolites, including C11-hydrocarbons, sulfur compounds and quinone derivatives, not usually found in marine seaweeds and described for the first time in the literature. Furthermore, several terpenes, steroids and halogenated compounds have been described. This chemical diversity gives it interesting biological properties, including cytotoxic, antimicrobial, antioxidant, anti-inflammatory and anti-herbivory activities. These findings highlight the importance to continue investigations on this genus and the need to compile the data available so far, since the species are quite heterogeneous, notably in relation to the chemical constitution. This paper reviews the literature on the Dictyopteris genus, focusing on its secondary metabolites and biological activities, in order to build the base for further studies.

Molecular networking prospection and characterization of terpenoids and C15-acetogenins in Brazilian seaweed extracts.

Molecular networking (MN) can efficiently dereplicate extracts and pure compounds. Red algae of the genus Laurencia are rich in halogenated secondary metabolites, mainly sesquiterpenes and C15-acetogenins. Brown algae of the genus Dictyopteris produce mainly C11-hydrocarbons, sesquiterpenes and sulfur-containing compounds, while Dictyota and Canistrocarpus are reported to contain mainly diterpenes. This study performs an exploratory MN analysis of 14 extracts from algae collected in Brazil (including the oceanic islands) and characterizes the secondary metabolites from the analyzed species. The extracts and some isolated metabolites were analyzed by LC-MS using the FastDDA algorithm, and the MS/MS spectra were submitted to GNPS and displayed in Cytoscape 3.5.1. The GNPS platform generated 68 individual nodes and nine family networks. The MN exploratory analysis indicated chemical differences among species, and also in sampling sites for the same species. For some extracts, it was possible to identify mass values that could correspond to terpenoids and C15-acetogenins that have already been isolated from those or related species. An interesting chemodiversity was highlighted between Laurencia catarinensis from two nearby islands, and this was revealed and was also suggested by the family networks. Many nodes in the MN could not be characterized, and these metabolites can be used as targets for isolation in future works.

Antimycoplasmic activity and seasonal variation of essential oil of Eugenia hiemalis Cambess. (Myrtaceae).

The purpose of this work was to study the chemical composition and antimycoplasmic and anticholinesterase activities of the essential oil of Eugenia hiemalis leaves collected throughout the year. A total of 42 compounds were identified by CG, and are present in almost every seasons. Sesquiterpenes were dominant (86.01-91.48%), and non-functionalised sesquiterpenes comprised the major fraction, which increased in the summer; monoterpenes were not identified. The major components were spathulenol (5.36-16.06%), δ-cadinene (7.50-15.93%), bicyclogermacrene (5.70-14.24%) and ß-caryophyllene (4.80-9.43%). The highest oil yield was obtained in summer and autumn. Essential oils presented activity against three evaluated Mycoplasma strains, but no activity was observed in the anticholinesterase assay.

C15 acetogenins from the Laurencia complex: 50 years of research – an overview

Abstract Acetogenins are secondary metabolites derived from the polyketide pathway and their potential role as chemotaxonomical markers for red algae belonging to the Laurencia complex has been long pointed out. C15 acetogenins from algae are quite different from plant acetogenins: they are usually halogenated, and have an enyne or a bromoallene terminal group. Since they were first reported, laurencin and other algal acetogenins have inspired great curiosity among natural product chemists and also those working with synthesis. This paper reviews the literature about C15 acetogenins, focusing on their distribution, chemical and biological aspects, including their reported biological activities.