Wilmar Maarisit

English

Tohoku Medical and Pharmaceutical University Academic Repository / 東北医科薬科大学学術リポジトリ

東北医科薬科大学 
審査学位論文（博士）要旨 
 
 
氏名（本籍） ｳｨﾙﾏｰ ﾏｱﾘｼｯﾄ Wilmar Maarisit（インドネシア） 
学位の種類 博士（薬科学） 
学位記番号 博薬科第 9 号 
学位授与の日付 平成 29 年 3 月 10 日 
学位授与の要件 学位規則第４条１項該当 
学位論文題名 
New Types of Protein Tyrosine Phosphatase 1B Inhibitors from 
Marine and Terrestrial Organisms 
論文審査委員 
主査 教 授 佐々木 健 郎 
副査 教 授 柴 田 信 之 
副査 教 授 浪 越 通 夫 
-1- 
 
New Types of Protein Tyrosine Phosphatase 1B Inhibitors from 
Marine and Terrestrial Organisms 
 
Tohoku Medical and Pharmaceutical University 
Department of Natural Product Chemistry 
 
Wilmar Maarisit 
 
Marine and terrestrial organisms are a rich source of biologically active metabolites and 
have been used for the development of new therapeutic agents and their lead compounds. In the 
course of the search for new types of protein tyrosine phosphatase (PTP) 1B inhibitors from 
marine and terrestrial organisms, the EtOH extract from fruiting bodies of a mushroom Rusulla 
lepida collected in Sendai, Japan and a marine sponge Petrosia sp. collected at Manado in North 
Sulawesi, Indonesia, were found to inhibit the PTP1B activity.  
PTPs, one of the major families of phosphatases, consist of more than 100 members 
including PTP1B and regulate various cellular functions. PTP1B plays a significant role in the 
insulin and leptin signal transduction pathways as a negative regulator. Therefore, the inhibitors 
of PTP1B are expected to be a new type of therapeutic agents for the type 2 diabetes mellitus 
and obesity. 
Chemical investigation on the mushroom R. lepida led to the isolation of three new  
terpenes, (24E)-3,4-seco-cucurbita-4,24-diene-3-hydroxy-26,29-dioic acid (1), (+)-1,2-
didehydro-9-hydroxy-aristlone (2) and (+)-12-hydroxy-aristlone (3), together with two known 
compounds, (24E)-3,4-seco-cucurbita-4,24-diene-3,26,29-trioic acid (4) and (+)-aristlone (5). 
The structures of new compounds (1-3) were assigned on the basis of their spectroscopic data. 
Compound 1 showed a moderate inhibitory activity against PTP1B with an IC50 value of              
20.4 μM. On the other hand, compound 4 potently inhibited the PTP1B activity with an IC50 
-2- 
 
value of 0.4 μM. Oleanolic acid, a positive control, showed the IC50 value of 1.1 μM in the same 
bioassay. 
Compounds 1 and 4 were not cytotoxic against five cancer cell lines, Huh-7 
(hepatocarsinoma), EJ-1 (bladder), A549 (lung adenocarcinoma), MCF-7 (breast 
adenocarcinoma), and K562 (erythroleukemia), at 50 μM.  
The selectivity against several PTPs was examined, and compound 4 inhibited the     
T-Cell PTP (TCPTP) activity similar to PTP1B and exhibited 3-fold greater selectivity against 
PTP1B than vaccinia H-1-related phosphatase (VHR), one of the dual specificity phosphatase. 
TCPTP is also a negative regulator of insulin and leptin signaling pathways, and recent 
studies indicated that dual inhibitors against PTP1B and TCPT are expected to be drug candidates 
without major side effects. Compound 4 may be a candidates of lead compound for the 
development of drugs for the type 2 diabetes and obesity. 
 
 
 
Structures of compounds 1-5 isolated from fruiting bodies of R. lepida 
-3- 
 
A new nortriterpene, named as sarasinoside S (6), was isolated from the EtOH extract 
of an Indonesia marine sponge Petrosia sp. together with four known sarasinosides A1 (7), I1 (8) 
and J (9). A known tetramic acid derivative, melophlin C (10), was obtained from the EtOH 
extract as an active component against PTP1B and showed the IC50 value of 14.6 μM. 
Compounds 6-9 did not inhibit the PTP1B activity at 15.2-16.0 μM and the cell proliferation of 
two human solid cancer cell lines, Huh-7 and A549, at 50 μM. The bioactivity of the other 
melophlin derivatives will be an interesting future study. 
The structure of new compound, sarasinoside S (6), was determined by the analysis of 
its spectroscopic data and comparison with the other sarasinoside derivatives. Sarasinoside S (6) 
is the first example of a nortriterpene with a degraded side chain in the sarasinoside family.   
   
 
Structures of compounds 6-10 isolated from an Indonesian marine sponge Petrosia sp.  
 
-4- 
 
References: 
 
1. Lee, J-S., Maarisit, W., Abdjul, D.B., Yamazaki, H., Takahashi, O., Kirikoshi, R., Kanno, S., 
Namikoshi, M. Structures and biological activities of triterpenes and sesquiterpenes obtained 
from Russula lepida. Phytochemistry, 2016, 127, 63-68. 
 
2. Maarisit, W., Yamazaki, H., Kanno, S., Tomizawa, A., Lee, J-S., Namikoshi, M. Protein 
tyrosine phosphatase 1B inhibitory properties of seco-cucurbitane triterpenes obtained from 
fruiting bodies of Russula lepida. J. Nat. Med., 2017, 71, 334-337. 
 
3. Maarisit, W., Yamazaki, H., Kanno, S., Tomizawa, A., Rotinsulu, H., Wewengkang, D.S., 
Sumilat, D.A., Ukai, K., Kapojos, M.M., Namikoshi, M. A tetramic acid derivative with 
protein tyrosine phosphatase 1B inhibitory activity and a new nortriterpene glycoside from 
the Indonesian marine sponge Petrosia sp. Bioorg. Med. Chem. Lett., in press, (e-pub a head 
of print 28 Dec 2016; DOI : http://dx.doi.org/10.1016/j.bmcl.2016.12.077). 
 


New Types of Protein Tyrosine Phosphatase 1B Inhibitors from Marine and Terrestrial Organisms

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New Types of Protein Tyrosine Phosphatase 1B Inhibitors from Marine and Terrestrial Organisms

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