Produktion mariner Naturstoffe aus der Klasse der Bengamide in Myxobakterien: Biosynthese und Struktur-Aktivitäts-Beziehungen

Bengamide, aus marinen Schwammen stammende und als Inhibitoren der Methionin-Aminopeptidase (MetAP) charakterisierte Naturstoffe, wurden intensiv als Wirkstoffe gegen Krebs erforscht. In einem multidisziplinaren Forschungsprojekt haben wir die Bereitstellung von Bengamiden uber Fermentation des terrestrischen Myxobakteriums M. virescens, die Aufklarung ihrer Biosynthese und die Optimierung ihrer Eigenschaften als Arzneistoff-Leitstrukturen untersucht. Die Charakterisierung des Biosyntheseweges zeigte auf, dass bakterielle Resistenz gegenuber Bengamiden durch Leu154 des myxobakteriellen MetAP-Proteins vermittelt wird, und ermoglichte den Transfer des gesamten Biosynthesegenclusters in den geeigneteren Produktionsstamm M. xanthus DK1622. Eine Kombination aus Semisynthese mikrobiell gewonnener Bengamide und Totalsynthese fuhrte zum optimierten Derivat 8 a. Die nanomolare zellulare Wirksamkeit und die hohe metabolische Stabilitat waren mit einer verbesserten Halbwertszeit in Mausen sowie mit Antitumor-Effizienz in einem Melanom-Mausmodell verbunden.

[1]  S. Lillioja,et al.  Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial , 2015, Diabetes, obesity & metabolism.

[2]  M. Cooper,et al.  Natural product and natural product derived drugs in clinical trials. , 2014, Natural product reports.

[3]  F. Sarabia,et al.  Chemistry and Biology of Bengamides and Bengazoles, Bioactive Natural Products from Jaspis Sponges , 2014, Marine drugs.

[4]  N. Dhanesha,et al.  Inhibition of the methionine aminopeptidase 2 enzyme for the treatment of obesity , 2014, Diabetes, metabolic syndrome and obesity : targets and therapy.

[5]  R. Müller,et al.  Microsclerodermins from terrestrial myxobacteria: an intriguing biosynthesis likely connected to a sponge symbiont. , 2013, Journal of the American Chemical Society.

[6]  F. Sarabia,et al.  Epi-, epoxy-, and C2-modified bengamides: synthesis and biological evaluation. , 2013, The Journal of organic chemistry.

[7]  K. Prasad,et al.  Enantiospecific total synthesis of (-)-bengamide E. , 2013, Chemistry, an Asian journal.

[8]  Zhong-Jun Li,et al.  Concise synthesis and antitumor activity of Bengamide E and its analogs , 2013 .

[9]  Tyler A. Johnson,et al.  Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries. , 2012, Bioorganic & medicinal chemistry.

[10]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[11]  S. Franzblau,et al.  Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidases by Bengamide Derivatives , 2011, ChemMedChem.

[12]  J. González‐Gallego,et al.  Methionine Aminopeptidases as Potential Targets for Treatment of Gastrointestinal Cancers and other Tumors , 2010 .

[13]  M. Marahiel,et al.  Working outside the protein‐synthesis rules: insights into non‐ribosomal peptide synthesis , 2009, Journal of peptide science : an official publication of the European Peptide Society.

[14]  A. Phillips,et al.  The halichondrins and E7389. , 2009, Chemical reviews.

[15]  Christian Hertweck.  Die biosynthetische Grundlage der Polyketid‐Vielfalt , 2009 .

[16]  C. Hertweck,et al.  The biosynthetic logic of polyketide diversity. , 2009, Angewandte Chemie.

[17]  Andrés Francesch,et al.  Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. , 2009, Natural product reports.

[18]  P. Dorrestein,et al.  Biosynthetic origin of natural products isolated from marine microorganism–invertebrate assemblages , 2008, Proceedings of the National Academy of Sciences.

[19]  F. Nan,et al.  Design, Synthesis, and Biological Evaluation of Caprolactam‐Modified Bengamide Analogues , 2008, ChemMedChem.

[20]  G. Giaccone,et al.  A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer , 2007, Anti-cancer drugs.

[21]  M. Sabio,et al.  Depletion of methionine aminopeptidase 2 does not alter cell response to fumagillin or bengamides. , 2004, Cancer research.

[22]  Sunkyu Kim,et al.  Proteomics-based Target Identification , 2003, Journal of Biological Chemistry.

[23]  K. Prasad,et al.  An expedient synthesis of LAF389, a bengamide B analogue , 2003 .

[24]  S. Zabludoff,et al.  Synthesis and antitumor activity of ester-modified analogues of bengamide B. , 2001, Journal of medicinal chemistry.

[25]  K. Bair,et al.  Bengamides revisited: new structures and antitumor studies. , 2001, The Journal of organic chemistry.

[26]  P. Crews,et al.  Bengamides, heterocyclic anthelmintics from a Jaspidae marine sponge , 1986 .

[27]  A. Bauer,et al.  Industrial natural product chemistry for drug discovery and development. , 2014, Natural product reports.

[28]  Michael G Thomas,et al.  Biosynthesis of polyketide synthase extender units. , 2009, Natural product reports.

[29]  T. Molinski,et al.  Drug development from marine natural products , 2009, Nature Reviews Drug Discovery.

[30]  P. Crews,et al.  Novel sponge-derived amino acids. 11. The entire absolute stereochemistry of the bengamides , 1990 .