Mail
UHA
mail uha

Pr. Jacques Eustache Fr 

   

Jacques.Eustache@uha.fr

Equipe COT

130, rue de la mer rouge

F-68200 MULHOUSE

Current research

New antimycobacterial agents

The development of resistance mechanisms to currently available antibiotics is largely responsible for the recent surge of tuberculosis and several opportunistic infections. As a result there is an important medical need for antibiotics working through new mechanisms. Our research project aims at synthesizing and evaluating two new types of potential therapeutic agents active against M tuberculosis, the causative agent of tuberculosis.

  1. Analogues of the mycobacterial arabinosyltransferases substrates. These enzymes play a key role in the biosynthesis of key components of the mycobacterial cell wall called arabinanes. Arabinosyltransferase inhibition is a promising approach to potential antibiotics , specifically acting against mycobacteria. s[15]
  2. Inhibition of mycobactin biosynthesis. In order to obtain iron, required for its metabolism, M. tuberculosis produces characteristic siderophores called mycobactins. In our group, we design and synthesize analogues of key biosynthetic precursors of these siderophores. Sugar-nucleotide analogues are being prepared and their potential as antimycobacterial agents is evaluated in collaboration with partners in Academia. [1, 2]

We are also interested in another type of mycobacteria, (M. ulcerans), the causative agent of Buruli ulcer, a highly debilitating disease widespread in certain developing countries (mainly sub-saharian Africa). Our program aims at synthesizing the mycolactones responsible for M ulcerans pathogenicity) and to identify analogues that would act as antagonists of this cytotoxic molecule.

Next angiogenesis inhibitors

Angiogenesis is the formation of new blood microvessels from preexisting blood vessels. Angiogenesis plays an important role in sustaining the development of embryonic tissues but rarely intervene in adult healthy tissues.

In certain circumstances, however, the development of new microvessels may be observed. It can be beneficial (wound healing) or, more often, detrimental (linked to tumor development or chronic inflammatory diseases).

The possibility of antitumoral therapies besed on the control of angiogenesis has been recently proposed. We synthesize new fumagillin analogues with the aim of identifying molecules that would be both structurally simpler and more active thant the parent molecule. [4, 9, 13]

Synthesis of tetrahydroisoquinoline type alkaloids

Tetrahydroisoquinoline type alkaloids (the best example is Ecteinascidin 543, currently undergoing phase II clinical studies) generally possess strong antitumoral / antibacterial properties. These molecules, however, are structurally complex and difficult to develop. Our work, in collaboration with Professor Y. Yamamoto (Tohoku University), has the following aims:

  • Development of new synthetic approaches towards the tetrahydroisoquinoline skeleton. [5]
  • Application of these approaches to the synthesis of new tetrahydroisoquinoline alkaloids and new analogues.
  • Biological evaluation of these new analogues as antitumoral / antibacterial agents.

Analogues of saponine OSW-1

In collaboration with prof. H. Nemoto's team (Toyama University) our project aims at synthesizing derivatives of the antitumor saponine OSW-1. This compound is more active than most established antitumor agents (including taxol) and seems to be less toxic (as measured in human lung cells). It features a steroid and a sugar moieties. We prepare analogues of this molecule, the Japanese team synthesizing the steroid skeleton while we take care of the sugar part. The biological activity is measured in Japan. [3]

Past research

Medicinal chemistry

NO synthetase inhibitors, lipid A-like immunostimulants, retinoids.

Organic chemistry

Carbohydrate and glycolipid chemistry, sulfur ylid chemistry, macrocycle synthesis.

Représentatives publications

  1. Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis.

    Miethke, M.; Bisseret, P.; Beckering, C.; Vignard, D.; Eustache, J.; Marahiel, M.A.

    FEBS Journal, 2006, 273, 409-419

  2. Copper-Mediated Cross-Coupling of H-Phosphonates with Vinyliodonium Salts: A Novel Very Mild Synthesis of 2-Arylvinylphosphonates.

    Thielges, S.; Bisseret, P; Eustache, J.

    Org. Lett., 2005, 7, 681-684

  3. Synthesis and Anti-tumor Activity of the Estrane Analogue of OSW-.

    Matsuya, Y.; Masuda,S.; Ohsawa,neuro3dN.; Tschamber,T.; Eustache, J.; Kamoshita, K.; Sukenaga, Y.; Nemoto, H.

    Eur. J. Org. Chem., 2005, 803-808

  4. Enantioselective approaches to Potential MetAP-2 reversible inhibitors.

    Rodeschini, V.; Van de Weghe, P.; Salomon, E.; Tarnus C.; Eustache, J.

    J. Org. Chem., 2005, 70, 2409-2412

  5. Controlled Synthesis of cis- or trans- Isomers of 1,3-Disubstituted - Tetrahydroisoquinolines and 2,5-Disubstituted - Pyrrolidines

    Eustache, J.; Kabuto, C.; Le Nouen, D.; Uyehara; H.; Van de Weghe,P.; Yamamoto, Y.

    J. Org. Chem., 2005, 70, 4043-4neuro3d053

  6. A simple spiro-epoxide as methionine aminopeptidase-2 inhibitor: synthetic problems and solutions.

    Rodeschini, V.; Van de Weghe, P.; Tarnus C.; Eustache, J.

    Tetrahedron Lett, 2005, 46, 6691-6695

  7. Metathesis Reactions. General Considerations

    Van de Weghe, P.; Eustache, J.; Cossy, J.

    Current Topics in Medicinal Chemistry, 2005, 5, 1461-1472

  8. The Application of Olefin Metathesis to the Synthesis of Biologically Active Macrocyclic Agents.

    Van de Weghe, P.; Eustache, J.; Cossy, J.

    Current Topics in Medicinal Chemistry, 2005, 5, 1495-1520

  9. MetAP-2 Inhibitors Based on the Fumagillin Structure. Side-Chain Modification and Ring Subsituted Analogs.

    Rodeschini, V., Boiteau, J-G., van de Weghe, P., Tarnus, C., Eustache, J.

    J. Org. Chem, 2004, 69, 357-373

  10. Electrophilic selenocyclisation in 2-ene-1,5-diols systems: unexpected oxetane vs. tetrahydrofuran formation.

    van de Weghe, P. ; Bourg, S. ; Eustache, J.

    Tetrahedron, 2003, 59, 7365-7376

  11. Silicon Tether-Aided Coupling Meneuro3dtathesis: Application to the Synthesis of Attenol A

    van de Weghe, P. ; Aoun, D. ; Boiteau, J.G. ; Eustache, J.

    Org. Lett., 2002, 4, 4105-4108

  12. Formation of dissymmetric eight-membered silalketals by RCM and their conversion to spiroketals

    Boiteau, J.G. ; van de Weghe, P. ; Eustache, J.

    Tetrahedron Lett., 2001, 42, 239-242

  13. A new, Ring Closing Metathesis-based synthesis of (-)-Fumagillol

    Boiteau, J.G. ; van de Weghe, P. ; Eustache, J.

    Org. Lett., 2001, 3, 2737-2740

Successive positions

Ecole Nationale Supérieure de Chimie de Mulhouse, Mulhouse, France

  • Professor, 1996 - today. (from 1997 to 2004) chair, laboratory for organic and bioorganic chemistry; (CNRS unit; UMR 7015)

Sandoz Forschungsinstitut, Vienne, Autriche

  • Section leader, Immunopharmacology department, Head of medicinal chemistry, 1988-1996

Galderma R&D Sophia-Antipolis, France

  • Group leader, Head of médicinal chemistry, 1981-1988

Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud-Orsay, France

  • Chargé de Recherches 1979-1981
  • Attaché de Recherches 1972-1979 *
  • Stagiaire de Recherches 1971-1972

*1972-1975, leave of absence: University of Abidjan (Côte d'Ivoire)

Education

University of Wisconsin, Madison, Wisconsin, USA

  • Postdoctoral research associate 1979-1980. 18 months (Prof. E. Vedejs)

Université Paris-Sud Orsay, Orsay, France

  • Thèse d'état 1972 then 1975-1978 (Prof. S. David).
  • Master 1969-1971 (Prof. S. David)
  • BS chemistry 1965-1968