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Natural Products as Lead Structures for Anticancer and Antibacterial Drug Discovery: SAR Evaluation of Zampanolide and Pyridomycin

Applicant Altmann Karl-Heinz
Number 149253
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Organic Chemistry
Start/End 01.04.2014 - 31.03.2017
Approved amount 612'908.00
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Keywords (7)

Pyridomycin; Cancer; Tuberculosis; Natural products; Natural product synthesis; Zampanolide; SAR

Lay Summary (German)

Lead
Zampanolid ist ein aus einem Meeresschwamm isolierter Naturstoff, der in sehr kleinen Mengen die Vermehrung von Krebszellen effizient unterdrücken kann. Die wachstumshemmende Wirkung beruht auf der Bindung des Zampanolids an gewisse Bestandteile des Zellskeletts, was schliesslich zu Störungen bei der Zellteilung führt. Substanzen mit dem Wirkmechanismus des Zampanolids spielen in der Krebstherapie ganz allgemein eine wichtige Rolle, werden aber in den letzten Jahren vermehrt auch auf ihr Potenzial bei der Behandlung neurodegenerativer Erkrankungen hin untersucht. Pyridomycin ist ein bakterieller Naturstoff mit einer ausgeprägten Hemmwirkung auf das Wachstum von Mycobacterium tuberculosis, dem Erreger der Tuberkulose. In Zusammenarbeit mit der Gruppe von Prof. Stewart Cole an der EPFL konnten wir den Wirkmechanismus des Pyridomycins aufklären. Die Substanz greift demnach am gleichen Zielprotein an wie das zu den wichtigsten Medikamenten gegen die Tuberkulose zählende Isoniazid.
Lay summary

Wir haben in einem früheren Projekt ein Verfahren zur Laborsynthese von Zampanolidentwickelt, dessen Isolierung aus dem produzierenden Schwamm sehr aufwändig istund nur Zugang zu sehr kleinen Substanzmengen ermöglicht. Im gegenwärtigenTeilprojekt geht es darum diese früher erarbeitete Synthesemethodik zurHerstellung einer ganzen Reihe von strukturell abgewandelten Varianten desZampanolids einzusetzen, die anschliessend auf ihre biologische Aktivität hinuntersucht werden sollen.  Diese Studien werdenzu einem verbesserten Verständnis der Struktur-Wirkungs-Beziehungen rund um dasZampanolid führen, die zum jetzigen Zeitpunkt nur sehr unvollständig erforschtsind. Diese Erkenntnisse könnten die Grundlage für die Entwicklung neuerWirkstoffkandidaten bilden, die vielleicht ein gegenüber dem Zampanolidverbessertes therapeutisches Potenzial aufweisen könnten.

Analog zu den geplanten Arbeiten zu Zampanolid, geht es in diesem  Teilprojekt um dieSynthese verschiedener Strukturanaloga des Pyridomycins, die dann auf ihrebiologische Aktivität hin untersucht werden sollen, in diesem Fall auf ihreHemmwirkung auf Tuberkulosebakterien. Diese Studien stellen eine Fortführungund Erweiterung bereits laufender Arbeiten zum Verständnis derStruktur-Wirkungs-Beziehungen des Pyridomycins dar. Dabei ist es das Ziel,Substanzen zu entwickeln, die ein gegenüber dem Pyridomycin verbessertesEigenschaftsprofil aufweisen  undvielleicht als neue Arzneimittelkandidaten zur Behandlung der Tuberkulose profiliertwerden könnten.
Direct link to Lay Summary Last update: 06.02.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Recent developments in natural product-based drug discovery for tuberculosis.
Dong Maryline, Pfeiffer Bernhard, Altmann Karl-Heinz (2017), Recent developments in natural product-based drug discovery for tuberculosis., in Drug discovery today, 22(3), 585-591.
On The Chemistry and Biology of the Marine Macrolides Zampanolide and Dactylolide
Altmann Karl-Heinz, Brütsch Tobias Glauser Simon, On The Chemistry and Biology of the Marine Macrolides Zampanolide and Dactylolide, Taylor & Francis, Boca Raton, FL, USA.

Collaboration

Group / person Country
Types of collaboration
Prof. John Miller, School of Chemical and Physical Sciences Victoria University of Wellington New Zealand (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. José Fernando Diaz/Centro de Investigaciones Biológicas, (CSIC) (Madrid) Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Michel Steinmetz/Paul-Scherrer-Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Stewart Cole/EPF Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
52nd Bürgenstock Conference on Stereochemistry Talk given at a conference Total Synthesis and Functional Exploration of Macrocyclic Natural Products 30.04.2017 Brunnen, Switzerland Altmann Karl-Heinz;
Seminar at the Insitut Pasteur/University of Lille Individual talk Total Synthesis and Functional Exploration of Macrocyclic Natural Products 15.03.2017 Lille, France Altmann Karl-Heinz;
MolTag Science Day Talk given at a conference Total Synthesis and Functional Exploration of Macrocyclic Natural Products 07.11.2016 Vienna, Austria Altmann Karl-Heinz;
SCS Fall Meeting 2016 Talk given at a conference Stereoselective Synthesis and Biological Evaluation of Highly Potent New (-)-Zampanolide Derivatives 15.09.2016 Zürich, Switzerland Brütsch Tobias;
GdCh Kolloquium University of Mainz Individual talk Total Synthesis and Biological Exploration of Macrocyclic Natural Products 21.07.2016 Mainz, Germany Altmann Karl-Heinz;
GdCH Kolloquium TU Braunschweig Individual talk Total Synthesis and Biological Exploration of Macrocyclic Natural Products 13.06.2016 Braunschweig, Germany Altmann Karl-Heinz;
VI EWDSY – Sixth European Workshop on Drug Synthesis Poster Dihydropyridomycins as New Antitubercular Agents: Synthesis and SAR Studies 15.05.2016 Siena, Italy Altmann Karl-Heinz; Dong Maryline;
Seminar at the University of Geneva Individual talk Total Synthesis and Biological Exploration of Macrocyclic Natural Products 24.03.2016 Geneva, Switzerland Altmann Karl-Heinz;
Beilstein Organic Chemistry Symposium 2015, NATURAL PRODUCTS Talk given at a conference Total Synthesis and Functional Exploration of Bioactive Natural Macrocycles 28.09.2015 Prien am Chiemsee , Germany Altmann Karl-Heinz;
XXXV Biannual Meeting of the Royal Chemical Society of Spain Talk given at a conference Synthesis of Macrocyclic Natural Products and their Functional Exploration 19.07.2015 La Coruña, Spain Altmann Karl-Heinz;
SCS Fall Meeting 2014 Poster Dihydropyridomycins as New Antitubercular Agents: Synthesis and SAR Studies 11.09.2014 Zürich, Switzerland Dong Maryline; Altmann Karl-Heinz;
SCS Fall Meeting 2014 Poster Synthesis and SAR of New des-THP Analogs of (-)-Dactylolide and (-)-Zampanolide 11.09.2014 Zürich, Switzerland Altmann Karl-Heinz; Brütsch Tobias;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Die Herausforderung neue Tuberkulosemedikamente zu entwickeln German-speaking Switzerland 2014

Associated projects

Number Title Start Funding scheme
117594 Synthesis and Biological Evaluation of Novel Epothilone Analogs and Conjugates and Prodrugs thereof 01.10.2007 Project funding (Div. I-III)
107876 Synthesis and biological evaluation of novel, epothilone analogs and conjugates and prodrugs thereof 01.10.2005 Project funding (Div. I-III)
175744 Natural Products as Lead Structures for Anticancer and Antibacterial Drug Discovery: SAR Evaluation of Zampanolide and Pyridomycin 01.10.2017 Project funding (Div. I-III)
143269 Natural Products as Lead Structures for Anticancer Drug Discovery: Synthesis and SAR of Rhizoxin Analogs 01.01.2013 Project funding (Div. I-III)
126511 Natural Products as Lead Structures for Anticancer Drug Discovery: Synthesis and SAR of Rhizoxin Analogs 01.01.2010 Project funding (Div. I-III)

Abstract

Zampanolide and pyridomycin are macrocyclic natural products of marine and bacterial origin, respectively, with significant biological activity against proteins that are clinically validated drug targets in cancer and tuberculosis. Zampanolide is a microtubule-stabilizing agent with potent in vitro antiproliferative activity against human cancer cells; pyridomycin is a potent inhibitor of the growth of Mycobacterium tuberculosis and it targets the mycobacterial NADH-dependent enoyl-[acyl-carrier-protein] reductase (InhA; also known as FabI) which is also the target of the anti-tuberculosis drugs isoniazid and ethionamide.While the chemistry of zampanolide has been investigated in some detail, much less effort has been expended on the synthesis of pyridomycin or related structures. More importantly, only limited data on structure-activity relationships (SAR) are currently available in both cases and the structural parameters governing target interactions and pharmacological activity are not well understood. The work proposed in this grant application aims at the elucidation of some key aspects of the zampanolide and pyridomycin SAR. These studies will build on prior work in our laboratory on the total synthesis of zampanolide and of a limited number of zampanolide and pyridomycin analogs. For zampanolide, this will include simplified, monocyclic structures derived from desTHP-zampanolide, which we have previously shown to retain sub-uM antiproliferative activity for the inhibition of cancer cell growth in vitro. The work on pyridomycin analogs will largely be based on the 2-1'-dihydropyridomicin structural template, which essentially retains all of the antimycobacterial activity of the natural product, but does not contain a synthetically challenging enol ester moiety. All zampanolide analogs will be assessed for interactions with the tubulin/microtubule system and the inhibition of human cancer cell proliferation in vitro; pyridomycin analogs will be tested for InhA-inhibitory activity and the inhibition of mycobacterial growth. Overall, the studies proposed in this grant application will (1) widen the scope of the synthetic chemistry around zampanolide- and pyridomycin-type structures and they will (2) expand our understanding of the structural parameters that govern the biological activity of these compounds. As such they could provide the basis for the development of new antitumor or antimycobacterial agents with improved pharmacological properties or technical feasibility over the natural products zampanolide and pyridomycin.
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