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Fukuda, Nagai, Kurihara, Kanamoto, and Tomoda: Graphiumins I and J, New Thiodiketopiperazines from the Marine-derived Fungus Graphium sp. OPMF00224
Original Article

Natural Product Sciences 2015;21(4):255-260.

Published online: 17 January 2015

DOI: https://doi.org/10.20307/nps.2015.21.4.255

Graphiumins I and J, New Thiodiketopiperazines from the Marine-derived Fungus Graphium sp. OPMF00224

Takashi Fukuda1, Kenichiro Nagai1, Yuko Kurihara2, Akihiko Kanamoto2, Hiroshi Tomoda1, ∗

1 Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan

2 OP BIO FACTORY Co., Ltd., 5 Uruma Sandpit, Okinawa 904-2234, Japan

∗Author for correspondence Hiroshi Tomoda, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Tel: +82-; E-mail: tomodah@pharm.kitasato-u.ac.jp

      Revised 30 June 201528 July 2015       Accepted 3 August 2015

Copyright © 2015 The Korean Society of Pharmacognosy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Two new thiodiketopiperazines (TDKPs), designated graphiumins I (1) and J (2), were isolated from the culture broth of the marine-derived fungus Graphium sp. OPMF00224 by solvent extraction, silica gel column chromatography, and HPLC. Their absolute structures were elucidated by spectroscopic analyses (1D and 2D NMR data, ROESY correlations, and CD data) and chemical methods. They were found to be structurally rare TDKPs with a phenylalanine-derived indolin substructure. Compounds 1 and 2 inhibited yellow pigment production by methicillin-resistant Staphylococcus aureus (MRSA) with IC50 values of 63.5 and 76.5 µg/ml, respectively, without inhibiting its growth, even at 250 µ g/ml.

Keywords: Thiodiketopiperazines, Marine-derived fungus, MRSA, Yellow pigment inhibitor

REFERENCES

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Fig. 1.
Structures of graphiumins I (1), J (2) and A (3).
nps-21-255f1.tif
Fig. 2.
1H-1H COSY (a), Key HMBC (a), NOE (b) correlations, and H-H coupling (c) of 1.
nps-21-255f2.tif
Fig. 3.
1H-1H COSY and Key HMBC correlations of 2.
nps-21-255f3.tif
Fig. 4.
Proposed biosynthetic pathway of graphiumins I (1) and J (2).
nps-21-255f4.tif
Table 1.
13C and 1H NMR spectroscopic data for graphiumins I (1) and J (2) in CDCl3
1 2
Position δCa δH mult (J in Hz)b δCa δH mult (J in Hz)b
1 160.4, s 169.2, s
2 75.7, s 69.9, s
3 34.2, t 4.15, dq (18.0, 1.0) 39.3, t 3.23, dt (17.0, 1.0)
3.10, dq (18.0, 1.5) 3.13, dt (17.0, 1.5)
4 113.1, s 108.9, s
5 139.7, d 6.69, q (2.0) 138.2, d 6.64, t (2.0)
6 141.6, d 6.35, dd (8.0, 2.0) 139.9, d 6.34, dd (8.0, 2.0)
7 105.0, d 4.61, dd (8.0, 1.5) 105.5, d 4.69, dd (8.0, 2.0)
8 69.9, d 5.86, dt (8.0, 1.5) 71.9, d 5.93, dt (8.5, 2.0)
9 63.0, d 5.18, dq (8.0, 1.5) 60.5, d 5.21, br d (8.5)
10
11 171.7, s 171.6, s
12 41.9, t 2.56, dd (17.0, 3.0) 42.1, t 2.56, dd (17.0, 3.0)
2.46, dd (17.0, 9.0) 2.47, dd (17.0, 9.0)
13 67.6, d 4.09, m 67.5, d 4.07, m
14 36.5, t 1.44, m 36.5, t 1.43, m
1.52, m 1.51, m
15 25.3, t 1.37, m 25.2, t 1.34, m
1.45, m 1.44, m
16 31.7, t 1.31, m 31.7, t 1.29, m
17 22.6, t 1.32, m 22.6, t 1.30, m
18 14.1, q 0.91, t (8.0) 14.0, q 0.89, t (8.0)
1' 162.8, s 164.3, s
2' 76.5, s 73.6, s
3' 35.6, t 4.32, br d (18.0) 39.9, t 3.74, d (17.0)
3.25 d (18.0) 3.44, d (17.0)
4' 128.1, s 131.4, s
5' 125.3, d 7.33, d (7.0) 116.2, d 6.82, d (7.0)
6' 125.9, d 7.21, t (7.0) 129.3, d 7.17, t (7.0)
7' 128.8, d 7.34, t (7.0) 118.4, d 6.92, d (7.0)
8' 115.8, s 7.93, d (7.0) 146.4, s
9' 138.1, s 126.7, s
2-SMe 15.1, q 2.36, s
2'-SMe 14.2, q 2.20, s
8'-OH 10.03, s
13-OH NDc NDc

a) Chemical shifts are shown with reference to CDCl3 as 77.0 ppm.

b) Chemical shifts are shown with reference to CDCl3 as 7.26 ppm.

c) ND: not detected

Table 2.
Summary of biological activities of graphiumins I (1) and J (2) against MRSA
Compound White zone (mm)a Growthb Y. P. prod.b,c
50 μ g 25 μ g (IC50 μ g/ml)
1 24 22 >250 63.5
2 23 20 >250 76.5
Citridone Ad 23 18 >30 11.1

a Paper disk method (8 mm disk).

b Liquid culture method.

c Y. P. prod.; Yellow pigment production.

d Positive control.15

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