Marine Diterpenes Research Articles

Unveiling the potential of marine-derived diterpenes from the order Alcyonacea as promising anti-obesity agents

Metabolic syndrome (MS) represents a global health challenge characterized by various metabolic disorders, including HOMA-IR (insulin resistance), obesity, dyslipidemia, and hypertension. In our pursuit of identifying natural alternatives for the development of effective and safe anti-obesity medications, we examined the potential of the methanolic extract of the Red Sea derived soft coral Sarcophyton glaucum, where serum levels of glucose, insulin, HOMA-IR, lipid profile, fetuin A and B, PTP1Β (Protein tyrosine phosphatase 1B), adropin and omentin were determined. Furthermore, the expression of the UCP1 (Uncoupling protein 1) and PPARGC1A (Peroxisome proliferator–activated receptor-g coactivator-1a) genes have been assessed, to evaluate the anti-obesity potential of S. glaucum organic extract. Our findings demonstrated a significant decrease in glucose, HOMA-IR, cholesterol, triglyceride, LDL-C, fetuin A and B, and PTP1Β levels, accompanied by a significant increase in insulin, HDL-C, adropin, omentin, UCP1, and PPARGC1A expression after treatment with the soft coral extract. These promising outcomes can be attributed to the remarkable ingredients present in the extract, which were further supported by histopathological findings. In addition, a virtual screening protocol including molecular docking (MDock) and Structure-Activity Relationships (SARs) of 27 marine diterpenes was also explored to identify potential PTP1Β inhibitors targeting simultaneously the catalytic site and allosteric site, as well as fetuin A modulators. Moreover, the six most promising predicted marine diterpenes (4, 8, 9, 10, 13 and 14) were investigated for their pharmacokinetic properties, druglike nature and medicinal chemistry friendliness using the SwissADME platform. Of these, four marine diterpenes (4, 8, 9, and 10) were predicted to exhibit the appropriate drug-like properties.

Integration of NMR studies, computational predictions, and in vitro assays in the search of marine diterpenes with antitumor activity.

Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane-binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.

Total Synthesis of (+)-Erogorgiaene and the Pseudopterosin A-F Aglycone via Enantioselective Cobalt-Catalyzed Hydrovinylation.

Due to their pronounced bioactivity and limited availability from natural resources, metabolites of the soft coral Pseudopterogorgia elisabethae, such as erogorgiaene and the pseudopterosines, represent important target molecules for chemical synthesis. We have now developed a particularly short and efficient route towards these marine diterpenes exploiting an operationally convenient enantioselective cobalt‐catalyzed hydrovinylation as the chirogenic step. Other noteworthy C−C bond forming transformations include diastereoselective Lewis acid‐mediated cyclizations, a Suzuki coupling and a carbonyl ene reaction. Starting from 4‐methyl‐styrene the anti‐tubercular agent (+)‐erogorgiaene (>98 % ee) was prepared in only 7 steps with 46 % overall yield. In addition, the synthesis of the pseudopterosin A aglycone was achieved in 12 steps with 30 % overall yield and, surprisingly, was found to exhibit a similar anti‐inflammatory activity (inhibition of LPS‐induced NF‐κB activation) as a natural mixture of pseudopterosins A−D or iso‐pseudopterosin A, prepared by β‐D‐xylosylation of the synthetic aglycone.

Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic.

Thrombosis related diseases are among the main causes of death and incapacity in the world. Despite the existence of antithrombotic agents available for therapy, they still present adverse effects like hemorrhagic risks which justify the search for new options. Recently, pachydictyol A, isopachydictyol A, and dichotomanol, three diterpenes isolated from Brazilian marine brown alga Dictyota menstrualis were identified as potent antithrombotic molecules through inhibition of thrombin, a key enzyme of coagulation cascade and a platelet agonist. Due to the biotechnological potential of these marine metabolites, in this work we evaluated their binding mode to thrombin in silico and identified structural features related to the activity in order to characterize their molecular mechanism. According to our theoretical studies including structure-activity relationship and molecular docking analysis, the highest dipole moment, polar surface area, and lowest electronic density of dichotomanol are probably involved in its higher inhibition percentage towards thrombin catalytic activity compared to pachydictyol A and isopachydictyol A. Interestingly, the molecular docking studies also revealed a good shape complementarity of pachydictyol A and isopachydictyol A and interactions with important residues and regions (e.g., H57, S195, W215, G216, and loop-60), which probably justify their thrombin inhibitor effects demonstrated in vitro. Finally, this study explored the structural features and binding mode of these three diterpenes in thrombin which reinforced their potential to be further explored and may help in the design of new antithrombotic agents.

Anti-HIV-1 activity of compounds derived from marine alga Canistrocarpus cervicornis

This paper describes the inhibition of human immunodeficiency virus-type 1 (HIV-1) virus replication in tumor cell lines by marine dolastanes (1–3) and secodolastane diterpenes (2) isolated from brown alga, Canistrocarpus cervicornis. Cells were exposed to CXCR4-tropic HIV-1 and treated with different concentrations of the compounds. We observed that the compounds inhibit HIV-1 replication in a dose-dependent manner with EC50 values of 0.35, 3.67, and 0.794 μM for diterpenes 1, 2, and 3, respectively. We demonstrate that these compounds present no cytotoxic effect with CC50 values ranging from 935 to 1910 μM. We also analyzed the virucidal effect of these compounds and observed that dolastane diterpenes 1 and 3 present a potent effect on a HIV-1 infectivity of up to 99 and 87 %, respectively, at a concentration of 25 μM. No virucidal effect was observed with secodolastane diterpene 2. Our results support further investigations on compounds 1 and 3 for pre-exposure prophylaxis (PrEP) and suggest that the microbicidal compounds act before virus penetration into target cells. We propose that these marine diterpenes could be considered as a potential HIV-1 therapy.

ChemInform Abstract: Two Rare‐Class Tricyclic Diterpenes with Antitubercular Activity from the Caribbean Sponge Svenzea flava. Application of Vibrational Circular Dichroism Spectroscopy for Determining Absolute Configuration.

Abstractisolation and structure elucidation of two new isoneoamphilectane‐based diterpenes

Two rare-class tricyclic diterpenes with antitubercular activity from the Caribbean sponge Svenzea flava. Application of vibrational circular dichroism spectroscopy for determining absolute configuration.

Two new natural products, 3 and 4, and their predecessor 7-isocyanoisoneoamphilecta-1(14),15-diene (2), of the rare isoneoamphilectane class of marine diterpenes, along with the known amphilectane diterpenes 6-8, were isolated from the n-hexane extract of the marine sponge Svenzea flava collected at Great Inagua Island, Bahamas. The molecular structures of compounds 3 and 4 were established by spectroscopic (1D/2D NMR, IR, UV, HRMS) methods and confirmed by a series of chemical correlation studies. In a first ever case study of the assignment of the absolute configuration of a molecule based on the isoneoamphilectane carbon skeleton, the absolute configuration of compound 5 was established as 3S,4R,7S,8S,11R,12S,13R by application of vibrational circular dichroism (VCD). In vitro anti-TB screenings revealed that metabolites 2-4 and, in particular, semisynthetic analogue 5, are strong growth inhibitors of Mycobacterium tuberculosis H37Rv.

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO–EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity.

An Enantioselective Total Synthesis of Helioporins C and E

A short and enantioselective total synthesis of helioporins C and E, which are bioactive marine diterpenes containing a serrulatane or amphilectane skeleton, was elaborated. The chirogenic step, i.e. a Cu(I)-catalyzed allylic alkylation of a cinnamyl chloride with methylmagnesium bromide, proceeded with virtually complete enantioselectivity (99% ee) in the presence of a chiral phosphine-phosphite ligand. The other stereocenters were diastereoselectively established through Me(2)AlCl-mediated cationic cyclization and Ir-catalyzed hydrogenation.

HIV-1 Reverse Transcriptase: a potential target for marine products

HIV-1 reverse transcriptase (HIV-1 RT) is a therapeutic target for the treatment of HIV-positive individuals or those already showing AIDS symptoms. In this perspective, the identification of new inhibitors for this enzyme is of great importance in view of the growing viral resistance to the existing treatments. This resistance has compromised the quality of life of those infected with multidrug-resistant strains, whose treatment options are already limited, putting at risk these individuals lives. The literature has recognized marine organisms and their products as natural sources for the identification of new therapeutic options for different pathologies. In this brief review, we consider the structure of HIV-1 RT and its most common inhibitors, as well as some marine diterpenes originally reported as HIV-1 RT inhibitors to encourage the identification and development of new marine antiviral prototypes.

Enantiospecific synthesis of the ABC and ABD ring systems of the marine diterpenes aberraranes

Enantiospecific synthesis of the ABC and ABD ring systems present in the marine diterpenes aberraranes, starting from the readily available ( S)-campholenaldehyde, has been accomplished.

Marine diterpene glycosides

Marine diterpene glycosides (MDGs) respresent a small but highly significant group of the much larger class of marine diterpenes. The three well-studied examples of MDGs are eleutherobins, pseudopterosins and fuscosides, all of which exhibit extremely promising biological activity. The eleutherobins are potent anti-mitotic agents, and the pseudopterosins and fuscosides are potent anti-inflammatory agents. This review discusses the structures and biological activities of these compounds, as well as their biosynthesis and synthesis.

Synthesis of Three of the Cladiellins

The cladiellins (eunicellins) are marine diterpenes with varying biological activity. Their interesting ether-bridged architecture has made them a popular synthetic target. However, this is the only approach to multiple members of the family with a (E)-configured alkene in the larger ring. This (E)-alkene is installed by the [2,3]-sigmatropic rearrangement of oxonium ylid D, prepared by rhodium-catalyzed decomposition of α-diazo ketone B.

A unified strategy for enantioselective total synthesis of cladiellin and briarellin diterpenes: total synthesis of briarellins E and F and the putative structure of alcyonin and revision of its structure assignment.

Enantioselective total syntheses of briarellin E (12) and briarellin F (13), as well as the structure originally proposed for the cladiellin diterpene alcyonin (10), have been realized. Comparison of the spectral data for synthetic 10, natural alcyonin, cladiellisin (33), and cladiellaperoxide (34), as well as chemical transformations of 10 and natural alcyonin, suggest that the structure of this coral metabolite is allylic peroxide 11. The unified approach detailed herein can be used to access both C4-deoxygenated and C4-oxygenated cladiellins and briarellins. The central step in these syntheses is acid-promoted condensation of (Z)-alpha,beta-unsaturated aldehydes 17 with cyclohexadienyl diols 18 to form intermediates 16 incorporating the hexahydroisobenzofuran core and five stereocenters of these marine diterpenes (Scheme 1 ).

Induction of apoptosis by diterpenes from the soft coral Xenia elongata.

Four new diterpenes ( 1- 4) were isolated from the soft coral Xenia elongata using a novel cell-based screen for apoptosis-inducing, potential anticancer compounds. The molecular structures of the diterpenes were determined using a combination of NMR and mass spectrometry. The bioactivities were confirmed using a specific apoptosis induction assay based on genetically engineered mammalian lines with differential, defined capacities for apoptosis. The diterpenes induce apoptosis in micromolar concentrations. This is the first report of apoptosis induction by marine diterpenes in xenicane skeletons.

Cycloamphilectenes, a new type of potent marine diterpenes: inhibition of nitric oxide production in murine macrophages

The inhibitory effect of a series of 6 cycloamphilectenes, novel marine diterpenes based on amphilectene skeletons and isolated from the Vanuatu sponge Axinella sp., on NO, PGE2 and TNFα production in murine peritoneal macrophages was studied. These compounds reduced potently nitric oxide production in a concentration-dependent manner with IC50 values in the submicromolar range (0.1–4.3 μM). Studies on intact cells and Western blot analysis showed that the more potent cycloamphilectenes reduced the expression of inducible nitric oxide synthase without affecting cyclo-oxygenase-2 expression. Among them cycloamphilectene 2, the unique compound bearing an exocyclic methylene group, was able to reduce NO production without affecting TNFα release. Cycloamphilectene 2, which is an inhibitor of the nuclear factor-kB pathway, exhibited topical anti-inflammatory activity.

Synthetic Studies on Norrisolide: Enantioselective Synthesis of the Norrisane Side Chain

Norrisolide (1) belongs to a family of marine diterpenes that are characterized by the assembly of a bicyclic core with a unique and highly oxygenated side chain (norrisane side chain). As a prelude to the synthesis of 1, we present herein a short, efficient, and enantioselective synthesis of the norrisane side chain 4. The synthetic route toward 4 departs from d-mannose and is short (11 steps), efficient, and enantioselective.

ChemInform Abstract: Pinnatins A—E: Marine Diterpenes of the Rare Gersolane Class Derived from a Photochemically Induced Rearrangement of a Conjugated 2,5‐Bridged Furanocembrane Precursor.

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Pinnatins A−E: Marine Diterpenes of the Rare Gersolane Class Derived from a Photochemically Induced Rearrangement of a Conjugated 2,5-Bridged Furanocembrane Precursor

A group of five highly functionalized polycyclic α,γ-disubstituted-α,β-unsaturated-γ-lactones (3−7) featuring a unique bicyclo [11.1.0] carbon skeleton joined in a trans fashion have been isolated from a Caribbean gorgonian, Pseudopterogorgia bipinnata. These rare marine diterpenoids can be regarded as representatives of the uncommon gersolane ring system. Two of the new metabolites, pinnatin A (3) and pinnatin B (4), showed significant differential antitumor activity in the National Cancer Institute's 60-cell-line tumor panel. The biogenesis of the pivotal metabolite pinnatin A (3) appears to involve a photochemically allowed [σ2a + π2a] cycloaddition process of a conjugated 2,5-bridged furanocembrane precursor. Structural assignments were accomplished through extensive spectroscopic analysis including 2D NMR, accurate mass measurements (HREIMS), X-ray crystallography, and chemical interconversions.

Chiral arene-Cr(CO) 3 complexes in organic synthesis: A short enantioselective total synthesis of putative helioporin D

The first total synthesis of a member of the helioporin class of marine diterpenes has been achieved. Starting from (4a S)-η 6-5,6-dimethoxytetralin-Cr(CO) 3 (≥99% e.e.) the target molecule (putative helioporin D) is obtained in a mere 8 steps in an excellent overall yield of 45%. The synthesis is based on the specific reactivity and stereochemistry of the arene-Cr(CO) 3 substructure and involves highly regio- and diastereoselective benzylic deprotonation / alkylation steps. The 6-methyl-5-hepten-2-yl sidechain is diastereoselectively introduced in a stereoconvergent manner by alkylation of a benzylic lithiated complex with the in situ generated triflate of ( R)-6-methyl-5-hepten-2-ol. The relative configuration of the alkylation product was confirmed by X-ray crystal structure analysis. As the NMR data of the synthetic target compound are not in agreement with those of natural helioporin D, the stereostructure of the latter has to be revised.