Callyaerins, Cyclic Peptides from the Indonesian Marine Sponge Callyspongia aerizusa with Potent and Selective Antitubercular Activity Georgios Daletos,1 Rainer Kalscheuer,2 Victor Wray,3 Peter Proksch1 1Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Universitaetsstrasse 1, 40225 Duesseldorf, Germany 2Institute for Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitaetsstrasse 1, 40225 Duesseldorf, Germany 3Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany Extraction and Isolation The MeOH extract of Callyspongia aerizusa was subjected to solvent-solvent partitioning to give nhexane, EtOAc and n-BuOH fractions. Column chromatography of the EtOAc fractions, using Sephadex LH-20 or silica 60M as stationary phase, followed by purification with semi-preparative reversed-phase HPLC afforded several callyaerin derivatives.1,2 Basic structure of callyaerins Ring Callyaerin R1 R2 R3 R4 R5 Sidechain R6 R7 R8 C1 C2 C3 C4 C5 Phe Gly A IIe Hyp Val IIe Leu Pro Pro Leu Pro Ile B IIe Hyp IIe Leu Pro Pro Leu Pro Ile C His Hyp Leu Leu Pro Pro Val Pro Leu D IIe Phe Pro Hyp Pro Leu Pro Ile Pro IIe IIe Gly Ile Ile IIe Val IIe Phe Gly Asn Ala IIe E Leu Pro Phe Phe Pro Pro F Val Pro Val Phe Pro Pro Leu Phe G Leu Pro Pro Pro Pro Leu Pro Phe Phe Phe H Val Pro Val Phe Pro Pro Leu Pro Ile Hyp is γ-hydroxyproline Anti-TB assay All compounds were investigated in vitro against: References 1. Ibrahim, S. R. M.; Min, C. C.; Teuscher, F.; Ebel, R.; Kakoschke, C.; Lin, W.; Wray, V.; Edrada-Ebel, R.; Proksch, P. Biorg. Med. Chem. 2010, 18, 4947-4956. 2. Ibrahim, S. R. M.; Edrada-Ebel, R.; Mohamed, G. A.; Youssef, D. T. A.; Wray, V.; Proksch, P. ARKIVOC 2008, (xii), 164-171. - Mycobacterium tuberculosis - THP-1 (human acute monocytic leukemia cell line) - MRC-5 (human fetal lung fibroblast cell line) Callyaerins showed moderate to strong activity towards M. tuberculosis making these compounds interesting candidates for further studies. Conclusions The basic structural unit of the callyaerins comprises a cyclic peptide with a linear peptide side chain, both of variable size, linked through a non-proteinogenic (Z)2,3-diaminoacrylic acid (DAA) functional group. Callyaerins contain an unusually high number of proline residues and hydrophobic amino acids (IIe, Leu and Phe), which may contribute to the increased biological activity of these peptides. Acknowledgments Financial support by BMBF (to P.P.) is gratefully acknowledged. This work was supported by the Research Commission of the Medical Faculty of the Heinrich-Heine-University Düsseldorf and by the Jürgen Manchot Foundation (to R.K.). We wish to acknowledge Dr. Nicole de Voogd (Leiden, Naturalis Biodiversity Center, Leiden, The Netherlands) for identification of the sponges. We are indebted to Mrs. C. Kakoschke (Helmholtz Centre for Infection Research, Braunschweig, Germany) and Dr. R. Hartmann (Institute of Complex Systems: Strukturbiochemie, Juelich, Germany) for recording NMR spectra. We wish to thank Dr. Elisabeth Ferdinandus (University Pattimura, Ambon) and Prof. Dr. Sumali Wiryowidagdo (University Hassanudin, Makassar), both from Indonesia, for their support and help during sponge collection.
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