Enigmazole C: A Cytotoxic Macrocyclic Lactone and Its Ring-Opened Derivatives from a New Species of Homophymia Sponge.

A new macrolide, enigmazole C (1), and two additional analogues, enigmazoles E (2) and D (3), were obtained from a new species of the Homophymia genus as part of an ongoing discovery program at PharmaMar to study cytotoxic substances from marine sources. The structures were fully characterized by cumulative analyses of NMR, IR, and MS spectra, along with density functional theory computational calculations. All three of the new compounds feature an unusual 2,3-dihydro-4H-pyran-4-one moiety, but only enigmazoles C (1) and D (3) showed cytotoxic activity in the micromolar range against A-549 (lung), HT-29 (colon), MDA-MB-231 (breast), and PSN-1 (pancreas) tumor cells.

A Simplified Population-Level Landscape Model Identifying Ecological Risk Drivers of Pesticide Applications, Part One: Case Study for Large Herbivorous Mammals.

Environmental risk assessment is a key process for the authorization of pesticides, and is subjected to continuous challenges and updates. Current approaches are based on standard scenarios and independent substance-crop assessments. This arrangement does not address the complexity of agricultural ecosystems with mammals feeding on different crops. This work presents a simplified model for regulatory use addressing landscape variability, co-exposure to several pesticides, and predicting the effect on population abundance. The focus is on terrestrial vertebrates and the aim is the identification of the key risk drivers impacting on mid-term population dynamics. The model is parameterized for EU assessments according to the European Food Safety Authority (EFSA) Guidance Document, but can be adapted to other regulatory schemes. The conceptual approach includes two modules: (a) the species population dynamics, and (b) the population impact of pesticide exposure. Population dynamics is modelled through daily survival and seasonal reproductions rates; which are modified in case of pesticide exposure. All variables, parameters, and functions can be modified. The model has been calibrated with ecological data for wild rabbits and brown hares and tested for two herbicides, glyphosate and bromoxynil, using validated toxicity data extracted from EFSA assessments. Results demonstrate that the information available for a regulatory assessment, according to current EU information requirements, is sufficient for predicting the impact and possible consequences at population dynamic levels. The model confirms that agroecological parameters play a key role when assessing the effect of pesticide exposure on population abundance. The integration of laboratory toxicity studies with this simplified landscape model allows for the identification of conditions leading to population vulnerability or resilience. An Annex includes a detailed assessment of the model characteristics according to the EFSA scheme on Good Modelling Practice.

Can Stereoclusters Separated by Two Methylene Groups Be Related by DFT Studies? The Case of the Cytotoxic Meroditerpenes Halioxepines.

QM/NMR-DFT (quantum mechanics combined with nuclear magnetic resonance parameters calculated by density functional theory approximations) studies allowed us to link two stereoclusters separated by two methylene groups present in the new meroditerpenes halioxepine B (2) and halioxepine C (3) and the known halioxepine (1), isolated from two Indonesian sponges of the genus Haliclona (Reniera). DP4 and DP4+ probabilities were used to discriminate the two diastereotopic arrangements of the two stereoclusters, whose unconnected relative configurations were determined by ROESY and J-based configurational analysis. To confirm the DFT studies, the full relative configuration of 1 was deduced using a mixture of benzene-d6 and pyridine-d5 as the NMR solvent. ROESY measurements connected the two stereoclusters and demonstrated that DFT calculations accurately predict the configuration when two methylenes separate the two stereoclusters. The different arrangements of the distant stereoclusters C-1/C-2/C-7 and C-10/C-15 for compounds 2 and 3 were deduced by DFT calculations and explained the opposite optical rotations observed for the two compounds. Halioxepines B (2) and C (3) display moderate cytotoxicity against different human cancer cell lines.

Streptenols F-I Isolated from the Marine-Derived Streptomyces misionensis BAT-10-03-023.

A marine-derived bacterium, Streptomyces misionensis BAT-10-03-123, has produced four new streptenol derivatives, F, G, H, and I (1-4), as well as the known streptenols A and C (5 and 6). Their planar structures were elucidated by detailed analysis of spectroscopic data. The absolute configurations of the new streptenol compounds were determined by chemical and spectroscopic methods, including Mosher's ester method. All of the compounds were tested for cytotoxicity against four selected cancer cell lines.

Cytotoxic Anomoian B and Aplyzanzine B, New Bromotyrosine Alkaloids from Indonesian Sponges.

Two new bromotyrosine derivatives, anomoian B (1) and aplyzanzine B (2), were isolated, respectively, from the organic extracts of a Verongida sponge belonging to the Hexadella genus and from a two-sponge association (Jaspis sp. and Bubaris sp.), both collected off the coast of Indonesia. The planar structure of 1 and 2 was determined by 1D and 2D NMR experiments and by high-resolution mass spectrometry, while their absolute stereochemistry was assigned by comparison with optical rotation values of known bromotyrosines and by chemical degradation. Both compounds showed moderate antiproliferative activity against a panel of different cancer cell lines. Their cytotoxic activity is facilitated through the induction of apoptosis, which is mediated neither by the generation of reactive oxygen species nor by the inhibition of histone deacetylases in these cell lines.

Lanesoic Acid: A Cytotoxic Zwitterion from Theonella sp.

Lanesoic acid (1) was isolated and characterized from Theonella sp. during PharmaMar's ongoing program to study cytotoxic substances from marine sources. Its planar structure, elucidated by spectral analysis (NMR, IR, UV, and MS), possesses an unusual skeleton containing a tetrahydropyrimidine cation that is stabilized as a zwitterion by an internal carboxylate counterion. The stereostructure of 1 was deduced from ROESY-NOESY, J-based configurational analysis (JBCA), and density functional theory (DFT) computational calculations fitted using the recently published DP4+ parameter. Compound 1 was moderately active and selective against pancreas PSN1 cells (IC50 = 8.9 µg/mL) and inactive against colon HT-29, breast MD-MB-23, and NSCLC lung tumor cells.