Deiske A. Sumilat

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. 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.

Euryspongins A-C, three new unique sesquiterpenes from a marine sponge Euryspongia sp.

Three new unique sesquiterpenes, euryspongins A-C (1-3), were isolated from a marine sponge Euryspongia sp. collected at Iriomote Island, Okinawa, Japan. Compound 1 possessed a bicyclic furanosesquiterpene structure with six- and eight-membered rings, whereas compounds 2 and 3 had an α,β-unsaturated-γ-lactone ring instead of the furan ring in 1. Only five natural products in this class have been reported, and compounds 1-3 are the sixth-eighth examples of natural products. Compounds 1-3 had no inhibition effect against PTP1B, an important target enzyme for the treatment of diabetes, while the dehydro derivative of 1 [dehydroeuryspongin A (4)] exhibited inhibitory activity (IC(50)=3.6 μM).

Absolute structures and bioactivities of euryspongins and eurydiene obtained from the marine sponge Euryspongia sp. collected at Iriomote Island.

Three unique sesquiterpenes, named euryspongins A-C (1-3), have been isolated from the marine sponge Euryspongia sp. The absolute configuration of 1 was assigned as (4R,6R,9S) by comparing its experimental Electronic Circular Dichroism (ECD) spectrum with the calculated ECD spectra of both enantiomers, and the absolute configurations of 2, 3 and artifact 4 were suggested on the basis of that of 1 by assuming common biogenesis of 1-3. These absolute configurations were opposite to those depicted in the previous communication. Further separation of the remaining fractions lead to the isolation of a new C11-polyketide, named as eurydiene (5), together with a known C11-polyketide, nakitriol (6). The structure of 5 was assigned on the basis of its spectroscopic data as a bicyclic alcohol with a diene side chain. Dehydroeuryspongin A (4) inhibited protein tyrosine phosphatase 1B (PTP1B), an important target enzyme for the treatment of type II diabetes and obesity, with an IC50 value of 3.58μM. Moreover, compound 4 did not inhibit the proliferation of human hepatoma Huh-7 cells at 100μM. One of the locations in which PTP1B has been detected is hepatocytes. Compounds 1-3, 5, and 6 were not active against PTP1B. The growth of human colon (HCT-15) and T-cell lymphoma (Jurkat) cells was not disturbed by compounds 1-6.

Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from the freshwater fungus Phoma sp.

Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from the freshwater fungus Phoma sp.

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. 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 3β 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.

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). 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.

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.

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 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.

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

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. 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.