Inhibitory effects of sesquiterpene lactones from the Indonesian marine sponge Lamellodysidea cf. herbacea on bone morphogenetic protein-induced osteoblastic differentiation.

A new unique sesquiterpene lactone, bicyclolamellolactone A (1), was isolated together with two known monocyclofarnesol-type sesquiterpenes, lamellolactones A (2) and B (3), from the Indonesian marine sponge Lamellodysidea sp. (cf. L.

Screening for Small Molecule Inhibitors of BMP-Induced Osteoblastic Differentiation from Indonesian Marine Invertebrates.

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder with heterotopic ossification (HO) in soft tissues. The abnormal activation of bone morphogenetic protein (BMP) signaling by a mutant activin receptor-like kinase-2 (ALK2) leads to the development of HO in FOP patients, and, thus, BMP signaling inhibitors are promising therapeutic applications for FOP. In the present study, we screened extracts of 188 Indonesian marine invertebrates for small molecular inhibitors of BMP-induced alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation in a C2C12 cell line stably expressing ALK2(R206H) (C2C12(R206H) cells), and identified five marine sponges with potent ALP inhibitory activities.

Epipolythiodiketopiperazine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma cf. brevicompactum.

The marine-derived fungus Trichoderma sp. TPU199 (cf. Trichoderma brevicompactum) produces pretrichodermamide A (1) and gliovirin (2), which possess a rare type of epipolythiodiketopiperazine (ETP) structure with a disulfide bridge between the α- and β-positions of two amino acid residues.

Production of an α-pyrone metabolite and microbial transformation of isoflavones by an Indonesian sp.

A benzyl-α-pyrone metabolite, streptpyrone A (), was obtained together with three known isoflavonoids, daidzein-7--α-l-rhamnoside (), genistein-7--α-l-rhamnoside (), and daidzein (), from the culture broth of an Indonesian actinomycete sp. TPU1401A. The structure of , elucidated based on its spectroscopic data, has been reported as a synthetic compound.

Absolute Structures of Wedelolide Derivatives and Structure-Activity Relationships of Protein Tyrosine Phosphatase 1B Inhibitory ent-Kaurene Diterpenes from Aerial Parts of Wedelia spp. Collected in Indonesia and Japan.

Two sesquiterpene lactones with the (9R)-eudesman-9,12-olide framework, wedelolides I and J, have been isolated together with five eudesmanolide sesquiterpenes and twelve ent-kaurene diterpenes from the aerial parts of Indonesian Wedelia prostrata. The absolute configurations of wedelolides I and J, proposed in the previous communication, were proven by comparing their experimental Electronic Circular Dichroism (ECD) spectra with the calculated ECD spectrum of wedelolide I. The phytochemical study on the aerial parts of Okinawan Wedelia chinensis led to the isolation of three other eudesmanolide sesquiterpenes in addition to the three sesquiterpenes and eleven diterpenes isolated from the Indonesian W.

Callyspongiamides A and B, sterol O-acyltransferase inhibitors, from the Indonesian marine sponge Callyspongia sp.

Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data.

Cladosporamide A, a new protein tyrosine phosphatase 1B inhibitor, produced by an Indonesian marine sponge-derived Cladosporium sp.

Cladosporamide A (1), a new protein tyrosine phosphatase (PTP) 1B inhibitor, was isolated together with a known prenylated flavanone derivative (2) from the culture broth of an Indonesian marine sponge-derived Cladosporium sp. TPU1507 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on 1D and 2D NMR data.

Oleanane triterpenes with protein tyrosine phosphatase 1B inhibitory activity from aerial parts of Lantana camara collected in Indonesia and Japan.

During the search for new protein tyrosine phosphatase (PTP) 1B inhibitors, EtOH extracts from the aerial parts of Lantana camara L. (lantana) collected at Manado (Indonesia) and two subtropical islands in Japan (Ishigaki and Iriomote Islands, Okinawa) exhibited potent inhibitory activities against PTP1B in an enzyme assay. Four previously undescribed oleanane triterpenes were isolated together with known triterpenes and flavones from the Indonesian lantana.

Anti-mycobacterial alkaloids, cyclic 3-alkyl pyridinium dimers, from the Indonesian marine sponge Haliclona sp.

Three new dimeric 3-alkyl pyridinium alkaloids, named haliclocyclamines A-C (1-3), were isolated together with five known congeners, cyclostellettamines A (4), B (5), C (6), E (7), and F (8), from the Indonesian marine sponge Haliclona sp. The structures of 1-3 were assigned based on their spectroscopic data (1D and 2D NMR, HRFABMS, ESIMS/MS, UV, and IR). Compounds 1-8 exhibited antimicrobial activities against Mycobacterium smegmatis with inhibition zones of 17, 10, 13, 14, 8, 8, 12, and 12mm, respectively, at 10μg/disc.

A new biphenyl ether derivative produced by Indonesian ascidian-derived Penicillium albobiverticillium.

A new biphenyl ether derivative, 2-hydroxy-6-(2'-hydroxy-3'-hydroxymethyl-5-methylphenoxy)-benzoic acid (1), was isolated together with the known benzophenone derivative, monodictyphenone (2), from a culture broth of Indonesian ascidian-derived Penicillium albobiverticillium TPU1432 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on NMR experiments. Compound 2 exhibited moderate inhibitory activities against protein tyrosine phosphatase (PTP) 1B, T cell PTP (TCPTP), and CD45 tyrosine phosphatase (CD45), whereas compound 1 modestly inhibited CD45 activity.

An anti-mycobacterial bisfunctionalized sphingolipid and new bromopyrrole alkaloid from the Indonesian marine sponge Agelas sp.

In the course of our studies on anti-mycobacterial substances from marine organisms, the known dimeric sphingolipid, leucettamol A (1), was isolated as an active component, together with the new bromopyrrole alkaloid, 5-bromophakelline (2), and twelve known congeners from the Indonesian marine sponge Agelas sp. The structure of 2 was elucidated based on its spectroscopic data. Compound 1 and its bis TFA salt showed inhibition zones of 12 and 7 mm against Mycobacterium smegmatis at 50 μg/disk, respectively, while the N,N'-diacetyl derivative (1a) was not active at 50 μg/disk.

Furanoterpenes, new types of protein tyrosine phosphatase 1B inhibitors, from two Indonesian marine sponges, Ircinia and Spongia spp.

Protein tyrosine phosphatase (PTP) 1B negatively regulates the insulin and leptin signaling pathways, and, thus, the clinical application of PTP1B inhibitors to the prevention and treatment of type 2 diabetes and obesity is expected. During our studies on PTP1B inhibitors, two furanosesterterpenes and a C21 furanoterpene were obtained as new types of PTP1B inhibitors from two Indonesian marine sponges. (7E, 12E, 20Z, 18S)-Variabilin (1) and (12E, 20Z, 18S)-8-hydroxyvariabilin (2) from Ircinia sp.

Lissoclibadin 1, a Polysulfur Aromatic Alkaloid from the Indonesian Ascidian Lissoclinum cf. badium, Induces Caspase-Dependent Apoptosis in Human Colon Cancer Cells and Suppresses Tumor Growth in Nude Mice.

Lissoclibadins, polysulfur aromatic alkaloids, were isolated from the Indonesian ascidian Lissoclinum cf. badium. Lissoclibadins 1 (1), 3 (2), 4 (3), 7 (4), 8 (5), and 14 (6) inhibited the growth of four human solid cancer cell lines: HCT-15 (colon adenocarcinoma), HeLa-S3 (cervix adenocarcinoma), MCF-7 (breast adenocarcinoma), and NCI-H28 (mesothelioma).

A tetramic acid derivative with protein tyrosine phosphatase 1B inhibitory activity and a new nortriterpene glycoside from the Indonesian marine sponge Petrosia sp.

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitors from marine organisms, the known tetramic acid derivative, melophlin C (1), was isolated as an active component together with the new nortriterpenoid saponin, sarasinoside S (2), and three homologues: sarasinosides A (3), I (4), and J (5), from the Indonesian marine sponge Petrosia sp. The structure of 2 was elucidated on the basis of its spectroscopic data. Compound 1 inhibited PTP1B activity with an IC value of 14.

Induced Production of Halogenated Epidithiodiketopiperazines by a Marine-Derived Trichoderma cf. brevicompactum with Sodium Halides.

Marine-derived Trichoderma sp. TPU199 (cf. T.

Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors from an Indonesian ascidian-derived Penicillium verruculosum.

Two new merosesquiterpenes, verruculides A (1) and B (2), were isolated from a culture broth of the Indonesian ascidian-derived Penicillium verruculosum TPU1311, together with three known congeners, chrodrimanins A (3), B (4), and H (5). The structures of 1 and 2 were assigned on the basis of their spectroscopic data (1D and 2D NMR, HRMS, UV, CD, and IR). Compound 2 had a linear sesquiterpene moiety and was considered to be the derivative of the biosynthetic precursor for 1 and 3-5.

Variabines A and B: new β-carboline alkaloids from the marine sponge Luffariella variabilis.

Two new β-carboline alkaloids, variabines A (1) and B (2), were isolated from the Indonesian marine sponge Luffariella variabilis. Their structures were elucidated from spectral data, and 1 was found to be a sulfonated derivative of 2. Although numerous β-carboline alkaloids have been isolated from natural sources to date, 1 is the first β-carboline derivative containing a sulfate group.

Spongiacidin C, a pyrrole alkaloid from the marine sponge Stylissa massa, functions as a USP7 inhibitor.

USP7, a deubiquitylating enzyme hydrolyzing the isopeptide bond at the C-terminus of ubiquitin, is an emerging cancer target. We isolated spongiacidin C from the marine sponge Stylissa massa as the first USP7 inhibitor from a natural source. This compound inhibited USP7 most strongly with an IC50 of 3.

Manzamine A, a marine-derived alkaloid, inhibits accumulation of cholesterol ester in macrophages and suppresses hyperlipidemia and atherosclerosis in vivo.

The formation of foam cells in macrophages plays an essential role in the progression of early atherosclerotic lesions and therefore its prevention is considered to be a promising target for the treatment of atherosclerosis. We found that an extract of the marine sponge Acanthostrongylophora ingens inhibited the foam cell formation induced by acetylated low-density lipoprotein (AcLDL) in human monocyte-derived macrophages, as measured based on the accumulation of cholesterol ester (CE). Bioassay-guided purification of inhibitors from the extract afforded manzamines.

A new dibenz[b,e]oxepine derivative, 1-hydroxy-10-methoxy-dibenz[b,e]oxepin-6,11-dione, from a marine-derived fungus, Beauveria bassiana TPU942.

1-Hydroxy-10-methoxy-dibenz[b,e]oxepin-6,11-dione (1) was obtained from the culture broth of a marine-derived fungus, Beauveria bassiana TPU942, isolated from a marine sponge collected at Iriomote Island in Okinawa, together with two known compounds, chrysazin (2) and globosuxanthone A (3). The structure of 1 was elucidated on the basis of its spectroscopic data (HREIMS, 1D and 2D NMR experiments including ¹H--¹H COSY, HMQC and HMBC spectra). Dibenz[b,e]oxepines are rare in nature, and only six natural products have been reported.

A polybromodiphenyl ether from an Indonesian marine sponge Lamellodysidea herbacea and its chemical derivatives inhibit protein tyrosine phosphatase 1B, an important target for diabetes treatment.

The ethanol extract of an Indonesian marine sponge Lamellodysidea herbacea inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), an important target enzyme for the treatment of type II diabetes. Bioassay-guided isolation yielded a known polybromodiphenyl ether (1) as a sole bioactive component. The structure of 1 was confirmed by spectroscopic data for 1 and its methyl ether derivative (2).

Siladenoserinols A-L: new sulfonated serinol derivatives from a tunicate as inhibitors of p53-Hdm2 interaction.

Siladenoserinols A-L were isolated from a tunicate as inhibitors of p53-Hdm2 interaction, a promising target for cancer chemotherapy. Their structures including the absolute configurations were elucidated to be new sulfonated serinol derivatives, each of which contains a 6,8-dioxabicyclo[3.2.

Manadosterols A and B, sulfonated sterol dimers inhibiting the Ubc13-Uev1A interaction, isolated from the marine sponge Lissodendryx fibrosa.

Two new dimeric sterols, manadosterols A (1) and B (2), were isolated from the marine sponge Lissodendryx fibrosa collected in Indonesia. The two compounds are comprised of two sulfonated sterol cores connected through the respective side chains. Manadosterols A (1) and B (2) inhibited the Ubc13-Uev1A interaction with IC(50) values of 0.

Hyrtioreticulins A-E, indole alkaloids inhibiting the ubiquitin-activating enzyme, from the marine sponge Hyrtios reticulatus.

Hyrtioreticulins A-E (1-5) were isolated from the marine sponge Hyrtios reticulatus, along with a known alkaloid, hyrtioerectine B (6). Structural elucidation on the basis of spectral data showed that 1, 2, and 5 are new tetrahydro-β-carboline alkaloids, while 3 and 4 are new azepinoindole-type alkaloids. Hyrtioreticulins A and B (1 and 2) inhibited ubiquitin-activating enzyme (E1) with IC(50) values of 0.