Germacrane sesquiterpenes from leaves of Eupatorium chinense inhibit protein tyrosine phosphatase
Yamazaki H, Tsuge H, Takahashi O, Uchida R
Bioorganic & Medicinal Chemistry Letters
Three new germacrane-type sesquiterpene lactones (1–3) were isolated alongside seven known related congeners (4–10) from the leaves of Eupatoriumchinense L. (Compositae). The planar structures of 1–3 were elucidated by their spectroscopic data, including 1D and 2D NMR spectra. The relative and absolute configurations of 1–3 were determined using NOESY experiments and electronic circular dichroism analyses. Compounds 1, 4, 5, and 7 inhibited protein tyrosine phosphatase (PTP) 1B activity with IC50 values of 25, 11, 28, and 24 µM, respectively. Among these, compound 4 exhibited an inhibitory effect on T-cell PTP (TCPTP) with an IC50 value of 25 µM. To our knowledge, this is the first study demonstrating the PTP inhibitory activity of the germacrane sesquiterpenes. The results show that compound 4 acts as an inhibitor of both PTP1B and TCPTP.
Three Bioactive Compounds Against Colony Formation of Chinese Hamster V79 Cells from an Indonesian Ascidian Didemnum sp.
Wewengkang DS, Rotinsulu H, Sumilat DA, Oda T, Yamazaki H, Ukai K, Namikoshi M.
Chem Nat Compd, 2021, 57, 592-593
Development of an in vivo-mimic silkworm infection model with Mycobacterium avium complex
Yagi A, Yamazaki H, Terahara T, Yang T, Hamamoto H, Imada C, Tomoda H, Uchida R
Drug Discoveries & Therapeutics, 2021,14(6):287-295
In vivo-mimic silkworm infection models with Mycobacterium avium and Mycobacterium intracellulare were newly established to evaluate the therapeutic effects of anti-M. avium complex (MAC) antibiotics. Silkworms raised at 37°C died within 72 hours of an injection of M. avium or M.intracellulare (2.5 × 10^7 colony-forming unit (CFU)/larva·g) into the hemolymph. Clinical anti-mycobacterial (tuberculosis) antibiotics were evaluated under these conditions. Clarithromycin, kanamycin, streptomycin, amikacin, and ciprofloxacin exerted therapeutic effects in a dose-dependent manner, which was consistent with those in the mouse model. Furthermore, three effective actinomycete culture broths were selected in the screening program of our microbial broth library using the silkworm model, and four active metabolites, ohmyungsamycins A and B (1 and 2), chartreusin (3), and griseoviridin (4), were identified. Among these compounds, 1 showed the lowest 50% effective dose (ED50) value (8.5 µg/larva·g), while 3 had the best ED50/minimum inhibitory concentration (MIC) ratio (7.4). These results indicate that silkworm models are a useful tool for identifying anti-MAC antibiotics candidates with veritable therapeutic effects.
Inhibitory effects of sesquiterpene lactones from the Indonesian marine sponge Lamellodysidea cf. herbacea on bone morphogenetic protein-induced osteoblastic differentiation
Ohte S, Yamazaki H, Takahashi O, Rotinsulu H, Wewengkang DS, Sumilat DA, Abdjul DB, Maarisit W, Kapojos MM, Zhang H, Hayashi F, Namikoshi M, Katagiri T, Tomoda H, Uchida R.
Bioorg Med Chem Lett. 2021, 35:127783
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.
小林 啓介、内田 龍児、福田 隆志、長光 亨、長井 賢一郎、供田 洋
化學工業, 2021, 72 (1), 28-37
第 63 回 天然有機化合物討論会，大阪，令和 3 年 9 月
真菌 Talaromyces cellulolyticus BF-0307 株が生産する新規SOAT阻害剤celludinone類に関する研究
関 怜子、大城 太一、福田 隆志、内田 龍児、供田 洋