Arthrinins A–D: Novel diterpenoids and further constituents from the sponge derived fungus Arthrinium sp.(Bioorganic & Medicinal Chemistry
Volume 19, Issue 15, 1 August 2011, Pages 4644-4651 )


Sherif S. Ebada(a), h, Barbara Schulz(b), Victor Wray(c), Frank Totzke(d), Michael H.G. Kubbutat(d), Werner E.G. Müller(e), Alexandra Hamacher(f), Matthias U. Kassack(f), Wenhan Lin(g) and Peter Proksch(a),

a Institut für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität, Geb. 26.23, Universitätsstrasse 1, D-40225 Düsseldorf, Germany

b Institut für Mikrobiologie, Technische Universität Carolo-Wilhelmina zu Braunschweig, Spielmannstrasse 7, D-38106 Braunschweig, Germany

c Biophysikalische Analytik Abteilung, Helmholz Zentrum für Infektionsforschung, Inhoffenstrasse 7, D-38124 Braunschweig, Germany

d ProQinase GmbH, Breisacher Strasse 117, D-79106 Freiburg, Germany

e Institute for Physiological Chemistry, University Medical Center of the Johannes-Gutenberg-University Mainz, Duesbergweg 6, D-55128 Mainz, Germany

f Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine Universität, Universitätsstrasse 1, Geb. 26.23, D-40225 Düsseldorf, Germany

g State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China

h Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity 1, 11566 Cairo, Egypt
Received 21 March 2011;
revised 25 May 2011;
accepted 2 June 2011.
Available online 20 June 2011.

Abstract

Bioassay-guided fractionation of a methanolic extract of the fungus Arthrinium sp., isolated from the Mediterranean sponge Geodia cydonium, afforded 10 natural products including five new diterpenoids, arthrinins A–D (1–4) and myrocin D (5). In addition, five known compounds were obtained, which included myrocin A (6), norlichexanthone (7), anomalin A (8), decarboxycitrinone (9) and 2,5-dimethyl-7-hydroxychromone (10). The structures of all isolated compounds were unambiguously elucidated based on extensive 1D and 2D NMR and HR-MS analyzes. The absolute configuration of arthrinins A–D (1–4) was established by the convenient Mosher method performed in NMR tubes and by interpretation of the ROESY spectra. Antiproliferative activity of the isolated compounds was assessed in vitro against four different tumor cell lines, including mouse lymphoma (L5178Y), human chronic myelogenous leukemia (K562), human ovarian cancer (A2780) and cisplatin-resistant ovarian cancer cells (A2780CisR), using the MTT assay. Norlichexanthone (7) and anomalin A (8) exhibited the strongest activities with IC50 values ranging from 0.40 to 74.0 μM depending on the cell line investigated. This was paralleled by the inhibitory activity of both compounds against 16 cancer related protein kinases including aurora-B, PIM1, and VEGF-R2. In vitro IC50 values of 7 and 8 against these three protein kinases ranged from 0.3 to 11.7 μM. Further investigation of the potential antitumoral activity of compounds 5–8 was performed in an in vitro angiogenesis assay against human umbilical vascular endothelial cells (HUVEC) sprouting induced by vascular endothelial growth factor A (VEGF-A). Anomalin A (8), myrocin D (5) and myrocin A (6) inhibited VEGF-A dependent endothelial cell sprouting with IC50 values of 1.8, 2.6 and 3.7 μM, respectively, whereas norlichexanthone (7) was inactive.


Keywords: Diterpenoid; Arthrinium; Cytotoxicity; Protein kinase inhibition; Antiproliferative