Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers.

Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers.

Accessing chemical diversity from the uncultivated symbionts of small marine animals.

Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea.

Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.

The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1.

Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction.

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry.

Marine natural products as inhibitors of cystathionine beta-synthase activity.

A library consisting of characterized marine natural products as well as synthetic derivatives was screened for compounds capable of inhibiting the production of hydrogen sulfide (H2S) by cystathionine beta-synthase (CBS). Eight hits were validated and shown to inhibit CBS activity with IC50 values ranging from 83 to 187μM. The majority of hits came from a series of synthetic polyandrocarpamine derivatives.

Myristicyclins A and B: antimalarial procyanidins from Horsfieldia spicata from Papua New Guinea.

An antimalarial screen for plants collected from Papua New Guinea identified an extract of Horsfieldia spicata as having activity. Isolation of the active constituents led to the identification of two new compounds: myristicyclins A (1) and B (2). Both compounds are procyanidin-like congeners of myristinins lacking a pendant aromatic ring.

Plakinamine M, a steroidal alkaloid from the marine sponge Corticium sp.

By means of bioassay-guided fractionation, a new steroidal alkaloid, plakinamine M (1), and the known compound, plakinamine L (2), with a unique acyclic side chain, were isolated from the marine sponge Corticium sp. collected from New Britain, Papua New Guinea. The structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS.

Single-molecule inhibition of human kinesin by adociasulfate-13 and -14 from the sponge Cladocroce aculeata.

Two merotriterpenoid hydroquinone sulfates designated adociasulfate-13 (1) and adociasulfate-14 (2) were purified from Cladocroce aculeata (Chalinidae) along with adociasulfate-8. All three compounds were found to inhibit microtubule-stimulated ATPase activity of kinesin at 15 µM by blocking both the binding of microtubules and the processive motion of kinesin along microtubules. These findings directly show that substitution of the 5'-sulfate in 1 for a glycolic acid moiety in 2 maintains kinesin inhibition.

Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F.

A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels.

Investigations of the marine flora and fauna of the Fiji Islands.

Over the past 30 years, approximately 140 papers have been published on marine natural products chemistry and related research from the Fiji Islands. These came about from studies starting in the early 1980s by the research groups of Crews at the University of California Santa Cruz, Ireland at the University of Utah, Gerwick from the Scripps Institution of Oceanography, the University of California at San Diego and the more recent groups of Hay at the Georgia Institute of Technology (GIT) and Jaspars from the University of Aberdeen. This review covers both known and novel marine-derived natural products and their biological activities.

Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.

As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method.

New tetromycin derivatives with anti-trypanosomal and protease inhibitory activities.

Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro).

Strongylophorine-8, a pro-electrophilic compound from the marine sponge Petrosia (Strongylophora) corticata, provides neuroprotection through Nrf2/ARE pathway.

Green plant-origin electrophilic compounds are a newly-recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although marine organisms frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown.

Challenge of large-scale motion for residual dipolar coupling based analysis of configuration: the case of fibrosterol sulfate A.

Fibrosterol sulfate A is a polysulfated bis-steroid with an atypical side chain. Due to the flexibility of the linker, large-scale motions that change dramatically the shape of the entire molecule are expected. Such motions pose major challenges to the structure elucidation and the correct determination of configuration.

3-bromohomofascaplysin A, a fascaplysin analogue from a Fijian Didemnum sp. ascidian.

A new fascaplysin analogue, 3-bromohomofascaplysin A (1), along with two known analogues, homofascaplysin A (2) and fascaplysin (3), were isolated from a Fijian Didemnum sp. ascidian. The absolute configurations of 3-bromohomofascaplysin A (1) and homofascaplysin A (2) were determined via experimental and theoretically calculated ECD spectra.

Araiosamines A-D: tris-bromoindole cyclic guanidine alkaloids from the marine sponge Clathria (Thalysias) araiosa.

Four new tris-bromoindole cyclic guanidine alkaloids, araiosamines A-D, were isolated from the methanol extract of a marine sponge, Clathria (Thalysias) araiosa, collected from Vanuatu. Their carbon skeletons delineate a new class of indole alkaloids apparently derived from a linear polymerization process involving a carbon-carbon bond formation. Comparison of the structures including the relative configurations suggests a common intermediate containing a dihydroaminopyrimidine moiety capable of undergoing various modalities of conjugate addition to yield unprecedented ring systems.

Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa.

Four new depsipeptides, mirabamides E-H (1-4), and the known depsipeptide mirabamide C (5) have been isolated from the sponge Stelletta clavosa, collected from the Torres Strait. The planar structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The absolute configurations were established by the advanced Marfey's method, NMR, and GC-MS.

Distinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance.

To understand better the endogenous sources of MHC class I peptide ligands, we generated an antigenic reporter protein whose degradation is rapidly and reversibly controlled with Shield-1, a cell-permeant drug. Using this system, we demonstrate that defective ribosomal products (DRiPs) represent a major and highly efficient source of peptides and are completely resistant to our attempts to stabilize the protein. Although peptides also derive from nascent Shield-1-sensitive proteins and "retirees" created by Shield-1 withdrawal, these are much less efficient sources on a molar basis.

Two ring-A-aromatized bile acids from the marine sponge Sollasella moretonensis.

Two ring-A-aromatized bile acids, 1 and 2, were isolated from the sponge Sollasella moretonensis, collected from the seabed of northern Queensland. Structures were assigned on the basis of extensive 1D and 2D NMR studies, as well as analysis by HRESIMS. Compound 2 has previously been produced synthetically, though this marks its first isolation from a natural source.

WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.

Wnt proteins are secreted post-translationally modified proteins that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number of dedicated factors in the secreting cell whose coordinated functions are not fully understood. A screen for small molecules identified inhibitors of vacuolar acidification as potent inhibitors of Wnt secretion.

Evaluation of pyridoacridine alkaloids in a zebrafish phenotypic assay.

Three new minor components, the pyridoacridine alkaloids 1-hydroxy-deoxyamphimedine (1), 3-hydroxy-deoxyamphimedine (2), debromopetrosamine (3), and three known compounds, amphimedine (4), neoamphimedine (5) and deoxyamphimedine (6), have been isolated from the sponge Xestospongia cf. carbonaria, collected in Palau. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS.

Fibrosterol sulfates from the Philippine sponge Lissodendoryx (Acanthodoryx) fibrosa: sterol dimers that inhibit PKCzeta.

Three new sulfated sterol dimers, fibrosterol sulfates A-C (1-3), have been isolated from the sponge Lissodendoryx (Acanthodoryx) fibrosa, collected in the Philippines. The structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1 and 2 inhibited PKCzeta with IC(50) values of 16.

Exocarpic acid inhibits mycolic acid biosynthesis in Mycobacterium tuberculosis.

Exocarpic acid (13 E-octadecene-9,11-diynoic acid) from Exocarpos latifolius R.Br. (Santalaceae) was previously shown to have specific antimycobacterial activity.

Anti-parasitic compounds from Streptomyces sp. strains isolated from Mediterranean sponges.

Actinomycetes are prolific producers of pharmacologically important compounds accounting for about 70% of the naturally derived antibiotics that are currently in clinical use. In this study, we report on the isolation of Streptomyces sp. strains from Mediterranean sponges, on their secondary metabolite production and on their screening for anti-infective activities.

Carteriosulfonic acids A-C, GSK-3beta inhibitors from a Carteriospongia sp.

Modulators of Wnt signaling have therapeutic potential in a number of human diseases. A fractionated library from marine invertebrates was screened in a luciferase assay designed to identify modulators of Wnt signaling. A fraction from a Carteriospongia sp.