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1.
Bioorg Med Chem Lett ; 35: 127783, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33422607

ABSTRACT

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. herbacea). The planar structure of 1 was assigned based on its spectroscopic data (1D and 2D NMR, HRESIMS, UV, and IR spectra). The relative and absolute configuration of 1 was determined by comparison of its calculated and experimental electronic circular dichroism spectra in combination with NOESY correlations. Compounds 1-3 inhibited bone morphogenic protein (BMP)-induced alkaline phosphatase activity in mutant BMP receptor-carrying C2C12 cells with IC50 values of 51, 4.6, and 20 µM, respectively.


Subject(s)
Bone Morphogenetic Proteins/antagonists & inhibitors , Lactones/pharmacology , Osteoblasts/drug effects , Porifera/chemistry , Sesquiterpenes/pharmacology , Alkaline Phosphatase/antagonists & inhibitors , Alkaline Phosphatase/metabolism , Animals , Bone Morphogenetic Proteins/metabolism , Cell Differentiation/drug effects , Cell Line , Dose-Response Relationship, Drug , Indonesia , Lactones/chemistry , Lactones/isolation & purification , Mice , Molecular Structure , Osteoblasts/metabolism , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Structure-Activity Relationship
2.
Mar Drugs ; 18(12)2020 Nov 30.
Article in English | MEDLINE | ID: mdl-33265937

ABSTRACT

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. The activity-guided purification of an EtOH extract of marine sponge Dysidea sp. (No. 256) resulted in the isolation of dysidenin (1), herbasterol (2), and stellettasterol (3) as active components. Compounds 1-3 inhibited ALP activity in C2C12(R206H) cells with IC50 values of 2.3, 4.3, and 4.2 µM, respectively, without any cytotoxicity, even at 18.4-21.4 µM. The direct effects of BMP signaling examined using the Id1WT4F-luciferase reporter assay showed that compounds 1-3 did not decrease the reporter activity, suggesting that they inhibit the downstream of the Smad transcriptional step in BMP signaling.


Subject(s)
Alkaline Phosphatase/antagonists & inhibitors , Cell Differentiation/drug effects , Dysidea/metabolism , Enzyme Inhibitors/pharmacology , Myoblasts, Skeletal/drug effects , Myositis Ossificans/drug therapy , Osteoblasts/drug effects , Osteogenesis/drug effects , Sterols/pharmacology , Thiazoles/pharmacology , Alkaline Phosphatase/metabolism , Animals , Bone Morphogenetic Protein 4/toxicity , Cell Line , Enzyme Inhibitors/isolation & purification , Indonesia , Mice , Molecular Structure , Myoblasts, Skeletal/metabolism , Myoblasts, Skeletal/pathology , Myositis Ossificans/metabolism , Myositis Ossificans/pathology , Osteoblasts/metabolism , Osteoblasts/pathology , Sterols/isolation & purification , Structure-Activity Relationship , Thiazoles/isolation & purification
3.
J Antibiot (Tokyo) ; 73(8): 559-567, 2020 08.
Article in English | MEDLINE | ID: mdl-32427947

ABSTRACT

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 ß-positions of two amino acid residues. We previously reported that this strain gave the halogenated ETPs, DC1149B (4), DC1149R (6), and iododithiobrevamide (7), when fermented with sodium halides (NaCl, NaBr, and NaI). Further analyses of the metabolites obtained under NaI-containing culture conditions resulted in the isolation of two new ETP derivatives (11 and 12) and three new trichothecene sesquiterpenes (13-15). The structures of 11 and 12, including their absolute configurations, were elucidated based on spectroscopic data for 11 and 12 and comparisons with those for 1 and related compounds, revealing that 11 was an epimer of 1 at the C-5 position and 12 was a trithio-derivative of 11. The structures of 13-15 were established by analyzing their 1D and 2D NMR data. The absolute configurations of 13-15 were assigned by comparing their experimental electronic circular dichroism (ECD) spectra with the calculated ECD spectrum of 13.


Subject(s)
Aquatic Organisms/chemistry , Hypocreales/chemistry , Piperazines/chemistry , Trichothecenes/chemistry , Circular Dichroism/methods , Fermentation/physiology , Sesquiterpenes/chemistry
4.
J Asian Nat Prod Res ; 22(8): 754-761, 2020 Aug.
Article in English | MEDLINE | ID: mdl-31311336

ABSTRACT

A benzyl-α-pyrone metabolite, streptpyrone A (1), was obtained together with three known isoflavonoids, daidzein-7-O-α-l-rhamnoside (2), genistein-7-O-α-l-rhamnoside (3), and daidzein (4), from the culture broth of an Indonesian actinomycete Streptomyces sp. TPU1401A. The structure of 1, elucidated based on its spectroscopic data, has been reported as a synthetic compound. However, this is the first report of the isolation of 1 as a metabolite of microbial origin. Strain TPU1401A exhibited the ability to transform the isoflavone aglycones 4 and genistein (5) into the 7-O-glycosides 2 and 3, respectively. Compounds 2 and 3 promoted the growth of strain TPU1401A more effectively than compounds 4 and 5. These results suggest that strain TPU1401A utilizes isoflavone glycosides to promote growth by transforming isoflavones through microbial glycosidation.


Subject(s)
Isoflavones , Streptomyces , Genistein , Indonesia , Molecular Structure , Pyrones
5.
Chem Pharm Bull (Tokyo) ; 66(6): 682-687, 2018.
Article in English | MEDLINE | ID: mdl-29863070

ABSTRACT

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. prostrata as above. However, the wedelolide derivatives found in the Indonesian plant were not detected. Among these compounds, most of the diterpenes inhibited protein tyrosine phosphatase (PTP) 1B activity, and a structure-activity relationship study revealed that the cinnamoyl group enhanced inhibitory activity. Therefore, two ent-kaurene derivatives with and without a cinnamoyl group were examined for the ability to accumulate phosphorylated-Akt (p-Akt) because PTP1B dephosphorylates signal transduction from the insulin receptor such as phosphorylated Akt, a key downstream effector. However, neither compound enhanced insulin-stimulated p-Akt levels in two human hepatoma cell lines (Huh-7 and HepG2) at non-cytotoxic doses.


Subject(s)
Diterpenes/pharmacology , Enzyme Inhibitors/pharmacology , Plant Components, Aerial/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Wedelia/chemistry , Cell Line, Tumor , Diterpenes/chemistry , Diterpenes/isolation & purification , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Hep G2 Cells , Humans , Indonesia , Japan , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 28(10): 1911-1914, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29631961

ABSTRACT

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. Compounds 1-3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays.


Subject(s)
Callyspongia/chemistry , Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Callyspongia/metabolism , Dipeptides/chemistry , Dipeptides/isolation & purification , Enzyme Assays , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Indonesia , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Magnetic Resonance Spectroscopy , Molecular Conformation , Sterol O-Acyltransferase/metabolism
7.
J Nat Med ; 72(3): 779-783, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29508256

ABSTRACT

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. Compound 1 modestly inhibited PTP1B and T-cell PTP (TCPTP) activities with IC50 values of 48 and 54 µM, respectively. The inhibitory activity of 2 against PTP1B (IC50 = 11 µM) was approximately 2-fold stronger than that against TCPTP (IC50 = 27 µM).


Subject(s)
Cladosporium/chemistry , Porifera/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Indonesia , Protein Tyrosine Phosphatase, Non-Receptor Type 1/therapeutic use
8.
Phytochemistry ; 144: 106-112, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28917090

ABSTRACT

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. The EtOH extracts of lantana collected in Ishigaki and Iriomote Islands exhibited different phytochemical profiles from each other and the Indonesian lantana. Triterpenes with a 24-OH group were isolated from the Indonesian lantana only. Five known triterpene compounds were detected in the Ishigaki lantana, and two oleanane triterpenes with an ether linkage between 3ß and 25 were the main components together with five known triterpenes as minor components in the Iriomote lantana. The structures of previously undescribed compounds were assigned on the basis of their spectroscopic data. Among the compounds obtained in this study, oleanolic acid exhibited the most potent activity against PTP1B, and is used as a positive control in studies on PTP1B.


Subject(s)
Enzyme Inhibitors/pharmacology , Lantana/chemistry , Oleanolic Acid/analogs & derivatives , Plant Components, Aerial/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Humans , Indonesia , Japan , Molecular Structure , Oleanolic Acid/chemistry , Oleanolic Acid/isolation & purification , Oleanolic Acid/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 27(15): 3503-3506, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28601525

ABSTRACT

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. Compounds 3 and 8 also modestly inhibited the activity of vaccinia H-1-related phosphatase (VHR), a dual-specificity phosphatase, at 17-18µM.


Subject(s)
Alkaloids/pharmacology , Anti-Bacterial Agents/pharmacology , Haliclona/chemistry , Mycobacterium Infections, Nontuberculous/microbiology , Mycobacterium smegmatis/drug effects , Pyridinium Compounds/pharmacology , Alkaloids/chemistry , Alkaloids/isolation & purification , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Indonesia , Mycobacterium Infections, Nontuberculous/drug therapy , Pyridinium Compounds/chemistry , Pyridinium Compounds/isolation & purification
11.
J Nat Med ; 71(4): 776-779, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28550651

ABSTRACT

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.


Subject(s)
Penicillium/chemistry , Phenyl Ethers/chemistry , Animals , Indonesia , Molecular Structure
12.
J Nat Med ; 71(3): 531-536, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28364227

ABSTRACT

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. Therefore, free amino groups are important for anti-mycobacterial activity. This is the first study to show the anti-mycobacterial activity of a bisfunctionalized sphingolipid. Compound 13 exhibited weak PTP1B inhibitory activity (29% inhibition at 35 µM).


Subject(s)
Agelas/chemistry , Anti-Bacterial Agents/pharmacology , Mycobacterium smegmatis/drug effects , Pyrroles/isolation & purification , Sphingolipids/pharmacology , Alkaloids/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Biological Products/chemistry , Biological Products/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Indonesia , Molecular Structure , Mycobacterium smegmatis/growth & development , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrroles/chemistry , Pyrroles/pharmacology , Sphingolipids/chemistry , Sphingolipids/isolation & purification , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 27(5): 1159-1161, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28189419

ABSTRACT

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. and furospongin-1 (3) from Spongia sp. inhibited PTP1B activity with IC50 values of 1.5, 7.1, and 9.9µM, respectively. The inhibitory activity of compound 1 against T-cell PTP (TCPTP) was approximately 2-fold that against PTP1B, whereas the vaccinia H-1-related phosphatase (VHR) inhibitory effects of 1 were 4-fold weaker than that of its PTP1B inhibitory activity. Compounds 1-3 at 50µM did not show cytotoxicity against two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1. Compound 1 did not enhance the phosphorylation level of Akt, a key downstream effector of the cascade, in Huh-7 cells.


Subject(s)
Enzyme Inhibitors/pharmacology , Furans/pharmacology , Porifera/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Proteins/pharmacology , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice, Knockout , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics
14.
J Nat Prod ; 80(2): 499-502, 2017 02 24.
Article in English | MEDLINE | ID: mdl-28181805

ABSTRACT

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). Lissoclibadin 1 (1) exerted the most potent cytotoxic effects in vitro and mainly promoted apoptosis through an intrinsic pathway with the activation of a caspase-dependent pathway in HCT-15 cells. In vivo studies demonstrated that 1 suppressed tumor growth in nude mice carrying HCT-15 cells without significant secondary adverse effects. In conclusion, the results obtained in the present study demonstrate that 1 has potential as a chemotherapeutic candidate for preclinical investigations.


Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspases/metabolism , Urochordata/chemistry , Adenocarcinoma , Alkaloids/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Female , HeLa Cells , Humans , Indonesia , MCF-7 Cells , Mice , Mice, Nude , Molecular Structure
15.
Bioorg Med Chem Lett ; 27(4): 999-1002, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28109786

ABSTRACT

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 A1 (3), I1 (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 IC50 value of 14.6µM, while compounds 2-5 were not active at 15.2-16.0µM. This is the first study to report the inhibitory effects of a tetramic acid derivative on PTP1B activity.


Subject(s)
Enzyme Inhibitors/pharmacology , Glycosides/pharmacology , Petrosia/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrrolidinones/pharmacology , Triterpenes/pharmacology , Animals , Enzyme Inhibitors/chemistry , Glycosides/chemistry , Humans , Inhibitory Concentration 50 , Marine Biology , Pyrrolidinones/chemistry , Triterpenes/chemistry
16.
J Nat Prod ; 78(10): 2319-21, 2015 Oct 23.
Article in English | MEDLINE | ID: mdl-26439145

ABSTRACT

Marine-derived Trichoderma sp. TPU199 (cf. T. brevicompactum) produced gliovirin (1), pretrichodermamide A (2), and trichodermamide A (3) in a freshwater medium. Compounds 1 and 2 are rare epidithiodiketopiperazines possessing an unusual disulfide linkage. In the seawater medium, the strain biosynthesized the 5-chloro-5-deoxy derivatives (4 and 5) of 3 and 2. The production of 5 was proportional to the concentration of seawater (NaCl). Therefore, 5-bromo-5-deoxy (6) and 5-deoxy-5-iodo (7) derivatives were biosynthesized in the freshwater media supplemented with NaBr and NaI, respectively. The structure of a new iodo derivative (7) was elucidated on the basis of its spectroscopic data.


Subject(s)
Dipeptides/isolation & purification , Piperazines/isolation & purification , Trichoderma/chemistry , Chromatography, High Pressure Liquid , Dipeptides/chemistry , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Palau , Piperazines/chemistry , Rhodophyta/microbiology , Sodium Chloride/analysis
17.
Bioorg Med Chem Lett ; 25(16): 3087-90, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26115570

ABSTRACT

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. Compounds 1, 3, and 5 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 8.4, 8.5, and 14.9 µM, respectively. Compound 2 showed 40% inhibition at 23.1 µM, while 4 was not active at 20.7 µM.


Subject(s)
Enzyme Inhibitors/chemistry , Penicillium/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Sesquiterpenes/chemistry , Urochordata/microbiology , Animals , Enzyme Inhibitors/isolation & purification , Indonesia , Magnetic Resonance Spectroscopy , Molecular Conformation , Penicillium/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Sesquiterpenes/isolation & purification
18.
J Nat Med ; 68(1): 215-9, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23686294

ABSTRACT

Two new ß-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 ß-carboline alkaloids have been isolated from natural sources to date, 1 is the first ß-carboline derivative containing a sulfate group. Compound 2 inhibited chymotrypsin-like activity of the proteasome and Ubc13 (E2)-Uev1A interaction with IC50 values of 4 and 5 µg/mL, respectively, whereas 1 had little effect on the activity or interaction.


Subject(s)
Alkaloids/isolation & purification , Carbolines/isolation & purification , Porifera/chemistry , Proteasome Inhibitors/pharmacology , Alkaloids/pharmacology , Animals , Carbolines/pharmacology , Humans , Liver/drug effects , Liver/enzymology , Molecular Structure , Proteasome Inhibitors/isolation & purification , Rats , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Ubiquitin-Conjugating Enzymes/antagonists & inhibitors , Ubiquitin-Conjugating Enzymes/metabolism
19.
Bioorg Med Chem ; 21(13): 3831-8, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23665143

ABSTRACT

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. Manzamine A was the most potent inhibitor of foam cell formation, and also suppressed CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2. In addition, manzamine A inhibited ACAT activity. Next, we orally administered manzamine A to apolipoprotein E (apoE)-deficient mice for 80 days, and found that total cholesterol, free cholesterol, LDL-cholesterol, and triglyceride levels in serum were significantly reduced and the area of atherosclerotic lesions in the aortic sinus was also substantially diminished. These findings clearly suggest that manzamine A suppresses hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting ACAT and is therefore a promising lead compound in the prevention or treatment of atherosclerosis. Although manzamine A has been reported to show several biological activities, this is the first report of a suppressive effect of manzamine A on atherosclerosis in vivo.


Subject(s)
Alkaloids/therapeutic use , Atherosclerosis/prevention & control , Carbazoles/therapeutic use , Cholesterol Esters/metabolism , Hyperlipidemias/prevention & control , Macrophages/drug effects , Alkaloids/chemistry , Alkaloids/isolation & purification , Animals , Atherosclerosis/blood , CHO Cells , Carbazoles/chemistry , Carbazoles/isolation & purification , Cells, Cultured , Cholesterol/blood , Cricetinae , Cricetulus , Foam Cells/drug effects , Foam Cells/metabolism , Humans , Hyperlipidemias/blood , Lipoproteins, LDL/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Porifera/chemistry , Sterol O-Acyltransferase/metabolism , Sterol O-Acyltransferase 2
20.
Bioorg Med Chem Lett ; 23(13): 3884-6, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23684893

ABSTRACT

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 3.8 µM among several USP family members tested.


Subject(s)
Porifera/chemistry , Protease Inhibitors/pharmacology , Pyrroles/pharmacology , Ubiquitin Thiolesterase/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protease Inhibitors/chemistry , Pyrroles/chemistry , Pyrroles/isolation & purification , Structure-Activity Relationship , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Specific Peptidase 7
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