2017
Oleanane triterpenes with protein tyrosine phosphatase 1B inhibitory activity from aerial parts of Lantana camara collected in Indonesia and Japan.
Abdjul DB, Yamazaki H, Maarisit W, Rotinsulu H, Wewengkang DS, Sumilat DA, Kapojos MM, Losung F, Ukai K, Namikoshi M.
Phytochemistry. 2017; 144: 106-112.
doi: 10.1016/j.phytochem.2017.08.020.
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 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.
Scopranones with Two Atypical Scooplike Moieties Produced by Streptomyces sp. BYK-11038.
Uchida R, Lee D, Suwa I, Ohtawa M, Watanabe N, Demachi A, Ohte S, Katagiri T, Nagamitsu T, Tomoda H.
Org Lett. 2017; 19: 5980-5983.
doi: 10.1021/acs.orglett.7b03003.
Abstract
Three new compounds, designated scopranones A-C, were isolated from the culture broth of a soil isolate, Streptomyces sp. BYK-11038, and shown to be inhibitors of bone morphogenetic protein (BMP) induced alkaline phosphatase activity in a BMP receptor mutant cell line. The structures were elucidated using NMR and other spectral data. The scopranones have an unusual structure with two atypical scooplike moieties linked at the tails to form part of a unique 3-furanone ring.
A new biphenyl ether derivative produced by Indonesian ascidian-derived Penicillium albobiverticillium.
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.
Anti-mycobacterial alkaloids, cyclic 3-alkyl pyridinium dimers, from the Indonesian marine sponge Haliclona sp.
Maarisit W, Abdjul DB, Yamazaki H, Kato H, Rotinsulu H, Wewengkang DS, Sumilat DA, Kapojos MM, Ukai K, Namikoshi M.
Bioorg Med Chem Lett. 2017; 27: 3503-3506.
doi: 10.1016/j.bmcl.2017.05.067.
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 12 mm, 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.
An anti-mycobacterial bisfunctionalized sphingolipid and new bromopyrrole alkaloid from the Indonesian marine sponge Agelas sp.
Abdjul DB, Yamazaki H, Kanno SI, Tomizawa A, Rotinsulu H, Wewengkang DS, Sumilat DA, Ukai K, Kapojos MM, Namikoshi M.
J Nat Med. 2017; 71: 531-536.
doi: 10.1007/s11418-017-1085-6.
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).
Callyspongiamides A and B, sterol O-acyltransferase inhibitors, from the Indonesian marine sponge Callyspongia sp.
Kapojos MM, Abdjul DB, Yamazaki H, Ohshiro T, Rotinsulu H, Wewengkang DS, Sumilat DA, Tomoda H, Namikoshi M, Uchida R.
Bioorg Med Chem Lett. 2018; 28: 1911-1914.
doi: 10.1016/j.bmcl.2018.03.077.
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.
A 2,4'-linked tetrahydroxanthone dimer with protein tyrosine phosphatase 1B inhibitory activity from the Okinawan freshwater Aspergillus sp.
Rotinsulu H, Yamazaki H, Miura T, Chiba S, Wewengkang DS, Sumilat DA, Namikoshi M.
J Antibiot. 2017; 70: 967–969.
doi: 10.1038/ja.2017.72.
No abstract available.
Anti-Mycobacterium activity of microbial peptides in a silkworm infection model with Mycobacterium smegmatis.
Yagi A, Uchida R, Hamamoto H, Sekimizu K, Kimura KI, Tomoda H.
J Antibiot. 2017; 70: 685-690.
doi: 10.1038/ja.2017.23.
Abstract
An in vivo-mimic silkworm infection model with Mycobacterium smegmatis was established. When silkworms were raised at 37 °C following an injection of M. smegmatis cells (1.25 × 10∧7 CFU/larva·g) into the silkworm hemolymph, they died within 48 h. Under these conditions, four microbial peptides with anti-M. smegmatis activity, lariatin A, calpinactam, lysocin E and propeptin, exerted therapeutic effects in a dose-dependent manner, and these are also clinically used agents that are active against Mycobacterium tuberculosis. These results indicate that the silkworm infection model with M. smegmatis is practically useful for the screening of therapeutically effective anti-M. tuberculosis antibiotics.
Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from a freshwater fungus Phoma sp.
Sumilat DA, Yamazaki H, Kanno S, Saito R, Watanabe Y, Namikoshi M.
J Antibiot. 2017; 70: 331–333.
doi: 10.1038/ja.2016.147
No abstract available.
A bromopyrrole-containing diterpene alkaloid from the Okinawan marine sponge Agelas nakamurai activates the insulin pathway in Huh-7 human hepatoma cells by inhibiting protein tyrosine phosphatase 1B.
Yamazaki H, Kanno SI, Abdjul DB, Namikoshi M.
Bioorg Med Chem Lett. 2017; 27: 2207-2209.
doi: 10.1016/j.bmcl.2017.03.033.
Abstract
Agelasine G (1), a known bromine-containing diterpene alkaloid, was isolated as a new type of protein tyrosine phosphatase (PTP) 1B inhibitor together with ageline B (2), an inactive debromo-derivative of 1, from the marine sponge Agelas nakamurai collected at Iriomote Island in Okinawa, Japan. Further biological evaluations revealed that compound 1 exhibited selective inhibitory activity against PTP1B over T-cell PTP and CD45 phosphatase. Compound 1 also enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells more strongly than compound 2. The results obtained in this study suggest that compound 1 activates the insulin signaling pathway by inhibiting PTP1B activity.
A New Pyranonaphtoquinone Derivative, 4-Oxo-rhinacanthin A, from Roots of Indonesian Rhinacanthus nasutus.
Maarisit W, Yamazaki H, Abdjul DB, Takahashi O, Kirikoshi R, Namikoshi M.
Chem Pharm Bull. 2017; 65: 586-588.
doi: 10.1248/cpb.c17-00074.
Abstract
A new pyranonaphthoquinone derivative, named 4-oxo-rhinacanthin A (1), was isolated from the roots of the Indonesian Rhinacanthus nasutus together with two known congeners, rhinacanthin A (2) and 3,4-dihydro-3,3-dimethyl-2H-naphtho[2,3-b]pyran-5,10-dione (3). The structure of 1 was elucidated based on its spectroscopic data. The absolute configuration of 1 was assigned by comparing its experimental Electronic Circular Dichroism (ECD) spectrum with the calculated ECD spectrum. Compounds 2 and 3 inhibited the growth of Staphylococcus aureus with inhibition zones of 16 and 20 mm at 25 µg/disc, respectively. Compound 3 also exhibited inhibitory activity against Mycobacterium smegmatis (20 mm at 25 µg/disc).
Furanoterpenes, new types of protein tyrosine phosphatase 1B inhibitors, from two Indonesian marine sponges, Ircinia and Spongia spp.
Abdjul DB, Yamazaki H, Kanno SI, Wewengkang DS, Rotinsulu H, Sumilat DA, Ukai K, Kapojos MM, Namikoshi M.
Bioorg Med Chem Lett. 2017; 27: 1159-1161.
doi: 10.1016/j.bmcl.2017.01.071.
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.
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.
Tatsuta T, Hosono M, Rotinsulu H, Wewengkang DS, Sumilat DA, Namikoshi M, Yamazaki H.
J Nat Prod. 2017; 80: 499-502.
doi: 10.1021/acs.jnatprod.6b01051.
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.
A tetramic acid derivative with protein tyrosine phosphatase 1B inhibitory activity and a new nortriterpene glycoside from the Indonesian marine sponge Petrosia sp.
Maarisit W, Yamazaki H, Kanno SI, Tomizawa A, Rotinsulu H, Wewengkang DS, Sumilat DA, Ukai K, Kapojos MM, Namikoshi M.
Bioorg Med Chem Lett. 2017; 27: 999-1002.
doi: 10.1016/j.bmcl.2016.12.077.
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.
Eudesmanolide sesquiterpenes and protein tyrosine phosphatase 1B Inhibitory ent-kaurane diterpenes from aerial parts of Indonesian Wedelia prostrata.
Abdjul DB, Yamazaki H, Maarisit W, Losung F, Rotinsulu H, Wewengkang DS, Sumilat DA, Namikoshi M.
Phytochem Lett. 2017; 20: 191–195.
Abstract
Seven eudesmanolide sesquiterpenes (1–7) and two ent-kaurene diterpenes (8 and 9) including two new (9R)-eudesman-9,12-olides, named wedelolides I and J (1 and 2), were isolated from the aerial parts of Indonesian Wedelia prostrata. The structures of 1 and 2 were assigned based on their spectroscopic data. Diterpenes 8 and 9 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 8.3 and 28 μM, respectively. Among sesquiterpenes 1–7, compound 4, wedelolide D, exhibited 32% inhibitory activity against PTP1B at 20 μM.
Protein tyrosine phosphatase 1B inhibitory properties of seco-cucurbitane triterpenes obtained from fruiting bodies of Russula lepida.
Abstract
The known seco-cucurbitane triterpene, (24E)-3,4-seco-cucurbita-4,24-diene-3,26,29-trioic acid (1), has been isolated as a potent protein tyrosine phosphatase (PTP) 1B inhibitor together with a new analogue, (24E)-3,4-seco-cucurbita-4,24-diene-3-hydroxy-26,29-dioic acid (2), from the fruiting bodies of Russula lepida. Further evaluation of their biological properties against PTPs revealed that compound 1 inhibited T-cell PTP activity similarly to PTP1B and exhibited moderate selectivity against PTP1B over vaccinia H-1-related phosphatase. Moreover, the in vitro growth inhibitory effects of 1 and 2 against three human cancer cell lines were examined in order to evaluate cell-based efficacy. However, neither 1 nor 2 enhanced insulin-stimulated p-Akt levels at non-cytotoxic concentrations.
第39回東北薬学セミナー (仙台) 平成 29 年 12 月
海洋生物由来protein tyrosine phosphatase 1B阻害剤に関する研究および培養法検討による新規糸状菌二次代謝産物の誘導生産
第35回メディシナルケミストリーシンポジウム (名古屋) 平成 29 年 10 月
FOP治療薬を指向した scopranone A の全合成及び構造活性相関研究
李 大葵，大多和 正樹，内田 龍児，供田 洋， 長光 亨
第 56 回日本薬学会東北支部大会 (青森) 平成 29 年 10 月
植物内生糸状菌 Cladosporium sp. TMPU1621株が生産する抗生物質に関する 研究
八木 瑛穂, 赤石 将成, 阿部 樹, 髙橋 健太, 千葉 聡美, 山﨑 寛之, 内田 龍児
＊優秀ポスター賞受賞
石垣島由来植物内生糸状菌 Aspergillus sp. TMPU1623 株が生産する新規protein tyrosine phosphatase 1B阻害剤
山﨑 寛之, 高橋 健太, 岩倉 夏樹, 赤石 将成, 阿部 樹, 千葉 聡美, 浪越 通夫, 内田 龍児
第 59 回天然有機化合物討論会 (札幌) 平成 29 年 9 月
インドネシア産 Wedelia prostata 由来新規セスキテルペンの構造および ent-kaurene 型ジテルペンの protein tyrosine phosphatase 1B 阻害活性
山﨑 寛之, Delfly B. Abdjul, 菅野 秀一, 桐越 亮太, 高橋 央宜, 浪越 通夫
日本生薬学会第64回年会，千葉，平成 29 年 9 月
西表島産海綿 Haliclona sp. より得られた新規 halichondriamine 類の構造と生物活性
山﨑 寛之, Delfly B. Abdjul, 桐越 亮太, 八木 瑛穂, 高橋 央宜, 内田 龍児, 浪越 通夫
日本薬学会第 137 年会，仙台，平成 29 年 3 月
パラオ産海洋糸状菌 Trichoderma cf. brevicompactum TPU199 株の NaI 添加培養による新規二次代謝産物の生産誘導
山﨑 寛之, 高橋 央宜, 桐越 亮太, 文屋 友希, 浪越 通夫
インドネシア産海洋糸状菌 Cladosporium sp. TPU1507 が生産する protein tyrosine phosphatase 1B 阻害剤
山﨑 寛之, Henki Rotinsulu, Defny S. Wewengkang, Deiske A. Sumilat, 菅井 紫乃, 鵜飼 和代, 浪越 通夫
An anti-mycobacterial sphingolipid and a new bromopyrrol alkaloid from an unidentified Indonesian marine sponge
Delfly B. Abdjul, Hiroyuki Yamazaki, Syu-ichi Kanno, Ayako Tomizawa, Henki Rotinsulu, Defny S. Wewengkang, Deiske A. Sumilat, Kazuyo Ukai, Magie M. Kapojos, Michio Namikoshi
Structures and biological activities of alkyl pyridinium alkaloids from an unidentified Indonesian marine sponge
Wilmar Maarisit, Delfly B. Abdjul, Hiroyuki Yamazaki, Hajime Kato, Henki Rotinsulu, Defny S. Wewengkang, Deiske A. Sumilat, Kazuyo Ukai, Magie M. Kapojos, Michio Namikoshi
カイコ感染モデルを用いた微生物由来の接合菌症治療薬の探索研究
富永 剛広、内田 龍児、供田 洋
土壌由来真菌が生産する新規 SOAT2 選択的阻害剤に関する研究
関 怜子、大城 太一、福田 隆志、内田 龍児、供田 洋
真菌 BF-0158 株が生産する新規 amphotericin B 増強活性物質に関する研究
八木 瑛穂、内田 龍児、供田 洋
＊学生優秀発表賞受賞 (口頭)
放線菌 Streptomyces sp. BYK11038 株が生産する骨形成因子シグナル阻害剤 scopranone 類に関する研究
内田龍児、諏訪いぶき、片桐岳信、供田 洋
FOP 治療薬の創製を目指したscopranone A の全合成ならびに誘導体合成
李 大葵、渡邊 望、大多和 正樹、下山 健太、内田 龍児、供田 洋、長光 亨