Antiproliferative effect of natural and semisynthetic polyethers from Laurencia viridis.

Squalene-derived polyethers are a unique class of compounds that display a great diversity of structures and a broad array of bioactivities, among which its notable antiproliferative activity stands out against various types of cancer cell lines. In this study, eighteen triterpene squalene-derived polyethers, including twelve natural products and six synthetic derivatives, obtained from the red alga Laurencia viridis Gil-Rodríguez & Haroun were screened for their antiproliferative activity against six cancer cell lines: A549, HBL-100, HeLa, SW1573, T-47D, and WiDr; and a structure-activity relationship (SAR) study was established.

Gongolarones as antiamoeboid chemical scaffold.

Free Living Amoeba (FLA) infections caused by Acanthamoeba genus include chronic nervous system diseases such as Granulomatous Amoebic Encephalitis (GAE), or a severe eye infection known as Acanthamoeba keratitis (AK). Current studies focused on therapy against these diseases are aiming to find novel compounds with amoebicidal activity and low toxicity to human tissues. Brown algae, such as Gongolaria abies-marina (previously known as Cystoseira abies-marina, S.G. Gmelin), presents bioactive molecules of interest, including some with antiprotozoal activity. In this study, six meroterpenoids were isolated and purified from the species Gongolaria abies-marina. Gongolarones A (1), B (2) and C (3) were identified as new compounds. Additionally, cystomexicone B (4), 1'-methoxyamentadione (5) and 6Z-1'-methoxyamentadione (6) were isolated. All compounds exhibited amoebicidal activity against Acanthamoeba castellanii Neff, A. polyphaga and A. griffini strains. Gongolarones A (1) and C (3) showed the lowest IC50 values against the two stages of these amoebae (trophozoite and cyst). Structure-activity relationship revealed that the cyclization by ether formation from C-12 to C-15 of 1, and the isomerization Δ2 t to Δ3 t of 3, increased the antiamoeboid activity of both compounds. Furthermore, gongolarones A (1) and C (3) triggered chromatin condensation, mitochondrial malfunction, oxidative stress, and disorganization of the tubulin-actin cytoskeleton in treated trophozoites. Moreover, transmission electron microscopy (TEM) images analysis revealed that compounds 1 and 3 induced autophagy process and inhibited the encystation process. All those results suggest that both compounds could induce programmed cell death (PCD) in Acanthamoeba.

Rare new bicyclic cembranoid ethers and a novel trihydroxy prenylated guaiane from the Xisha soft coral Lobophytum sp.

Seven new cembrane-type diterpenes, lobophytolins C-I (3-9), and one new prenylated-guiane-type diterpene, lobophytolin J (10), along with six known related ones (1, 2, 11-14), have been isolated from the soft coral Lobophytum sp. collected off the Xisha Island in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis and quantum mechanical (QM)-NMR methods. The absolute configuration of lobophytolin H (8) was determined by the application of the modified Mosher's method and chemical transformation. Lobophytolin D (4) exhibited promising cytotoxicities in in vitro bioassays against HT-29, Capan-1, A549, and SNU-398 human cancer cell lines with IC50 values of 4.52, 6.62, 5.17, and 6.15 µM, respectively.

Antiprotozoal activities of marine polyether triterpenoids.

Chagas disease and leishmaniasis are tropical neglected diseases caused by kinetoplastids protozoan parasites of Trypanosoma and Leishmania genera, and a public health burden with high morbidity and mortality rates in developing countries. Among difficulties with their epidemiological control, a major problem is their limited and toxic treatments to attend the affected populations; therefore, new therapies are needed in order to find new active molecules. In this work, sixteen Laurencia oxasqualenoid metabolites, natural compounds 1-11 and semisynthetic derivatives 12-16, were tested against Leishmania amazonensis, Leishmania donovani and Trypanosoma cruzi. The results obtained point out that eight substances possess potent activities, with IC50 values in the range of 5.40-46.45 µM. The antikinetoplastid action mode of the main metabolite dehydrothyrsiferol (1) was developed, also supported by AFM images. The semi-synthetic active compound 28-iodosaiyacenol B (15) showed an IC50 5.40 µM against Leishmania amazonensis, turned to be non-toxic against the murine macrophage cell line J774A.1 (CC50 > 100). These values are comparable with the reference compound miltefosine IC50 6.48 ±â€¯0.24 and CC50 72.19 ±â€¯3.06 µM, suggesting that this substance could be scaffold for development of new antikinetoplastid drugs.

Evaluation of Oxasqualenoids from the Red Alga Laurencia viridis against Acanthamoeba.

Acanthamoeba genus is a widely distributed and opportunistic parasite with increasing importance worldwide as an emerging pathogen in the past decades. This protozoan has an active trophozoite stage, a cyst stage, and is dormant and very resistant. It can cause Acanthamoeba keratitis, an ocular sight-threatening disease, and granulomatous amoebic encephalitis, a chronic, very fatal brain pathology. In this study, the amoebicidal activity of sixteen Laurencia oxasqualenoid metabolites and semisynthetic derivatives were tested against Acanthamoeba castellanii Neff. The results obtained point out that iubol (3) and dehydrothyrsiferol (1) possess potent activities, with IC50 values of 5.30 and 12.83 µM, respectively. The hydroxylated congeners thyrsiferol (2) and 22-hydroxydehydrothyrsiferol (4), active in the same value range at IC50 13.97 and 17.00 µM, are not toxic against murine macrophages; thus, they are solid candidates for the development of new amoebicidal therapies.

Combining the Power of J Coupling and DP4 Analysis on Stereochemical Assignments: The J-DP4 Methods.

A systematic study to include 3 JHH couplings into DP4 formalism ( J-DP4) led to the development of three alternative strategies. The d J-DP4 (direct) approach involves a new DP4-like equation including an additional probability term given by 3 JHH. The i J-DP4 (indirect) approach explores the original DP4 method with a restricted conformational search. Despite both strategies performing better than DP4, their combined use (i J/d J-DP4) provided the best results, with a 2.5-fold performance improvement at similar or lower computational cost.

Marine Microalgae: Promising Source for New Bioactive Compounds.

The study of marine natural products for their bioactive potential has gained strength in recent years. Oceans harbor a vast variety of organisms that offer a biological and chemical diversity with metabolic abilities unrivalled in terrestrial systems, which makes them an attractive target for bioprospecting as an almost untapped resource of biotechnological applications. Among them, there is no doubt that microalgae could become genuine "cell factories" for the biological synthesis of bioactive substances. Thus, in the course of inter-laboratory collaboration sponsored by the European Union (7th FP) into the MAREX Project focused on the discovery of novel bioactive compounds of marine origin for the European industry, a bioprospecting study on 33 microalgae strains was carried out. The strains were cultured at laboratory scale. Two extracts were prepared for each one (biomass and cell free culture medium) and, thus, screened to provide information on the antimicrobial, the anti-proliferative, and the apoptotic potential of the studied extracts. The outcome of this study provides additional scientific data for the selection of Alexadrium tamarensis WE, Gambierdiscus australes, Prorocentrum arenarium, Prorocentrum hoffmannianum, and Prorocentrum reticulatum (Pr-3) for further investigation and offers support for the continued research of new potential drugs for human therapeutics from cultured microalgae.

Marine Longilenes, Oxasqualenoids with Ser-Thr Protein Phosphatase 2A Inhibition Activity.

The red seaweed Laurencia viridis is a rich source of oxygenated secondary metabolites that were derived from squalene. We report here the structures of three novel compounds, (+)-longilene peroxide (1), longilene (2), and (+)-prelongilene (3) that were isolated from this alga, in addition to other substances, 4 and 5, resulting from their acid-mediated degradation. The effect of compounds 1 and 3 against Ser-Thr protein phosphatase type 2A (PP2A) was evaluated, showing that (+)-longilene peroxide (1) inhibited PP2A (IC50 11.3 μM). In order to explain the interaction between PP2A and compounds 1 and 3, molecular docking simulations onto the PP2A enzyme-binding region were used.

Pinnatifidenyne-Derived Ethynyl Oxirane Acetogenins from Laurencia viridis.

Red algae of Laurencia continue to provide wide structural diversity and complexity of halogenated C15 acetogenin medium-ring ethers. Here, we described the isolation of three new C15 acetogenins (3-5), and one truncated derivative (6) from Laurencia viridis collected on the Canary Islands. These compounds are interesting variations on the pinnatifidenyne structure that included the first examples of ethynyl oxirane derivatives (3-4). The structures were elucidated by extensive study of NMR (Nuclear Magnetic Resonance) data, J-based configuration analysis and DFT (Density Functional Theory) calculations. Their antiproliferative activity against six human solid tumor cell lines was evaluated.

New oxidized zoanthamines from a Canary Islands Zoanthus sp.

Three new norzoanthamine-type alkaloids, named 2-hydroxy-11-ketonorzoan thamide B (1), norzoanthamide B (2) and 15-hydroxynorzoanthamine (3), were isolated from Zoanthus sp. specimens collected at the Canary Islands. Their structures were determined by interpretation of NMR and HR-ESIMS data. Relative configurations of their chiral centers were proposed on the basis of ROESY spectra and by comparison of their spectroscopic data with those of the well-known compound, norzoanthamine.

Connecting discrete stereoclusters by using DFT and NMR spectroscopy: the case of nivariol.

The structural determination of small organic molecules is mainly undertaken by using NMR techniques, although it is increasingly supplemented by using computational methods. NMR parameters, such as chemical shifts and coupling constants, are extremely sensitive indicators of local molecular conformation and are a source of structural evidence. However, their interpretation is fairly challenging in many circumstances, such as the case of the new polyether squalene derivative nivariol, the structure of which was elucidated by means of NMR spectroscopy and DFT calculations. The potential flexibility of this molecule and the high number of quaternary carbon atoms that it contains make its configurational assignment very difficult. Moreover, the relative configuration of four separated stereoclusters was established and subsequently connected by using NOE and J-based analysis, as well as by a comparison of its experimental (13)C NMR chemical shifts with the corresponding population-weighted values, as calculated by using DFT methods. Limitations of these used approaches became apparent but were overcome by combining the two methods.

Corozalic acid: a key okadaic acid biosynthetic precursor with phosphatase inhibition activity.

Toxin precursors: Corozalic acid, a new Ser/Thr protein phosphatase 1 and 2A inhibitor that turned out to be a key metabolic intermediate, was isolated from cultures of the marine dinoflagellate Prorocentrum belizeanum. Detailed spectroscopic analysis and extensive computational calculations revealed its structure and conformational behavior. In addition, a comprehensive picture of the interactions of corozalic acid with PP1 and PP2A is proposed (see figure) on the basis of ab initio, docking and molecular dynamics calculations.