Laurent Commeiras

On the construction of 2-substituted 1,4-diacetoxybutadiene moiety: application to the synthesis of (±)-caulerpenyne

Abstract The synthesis of 2-substituted 1,4-diacetoxybutadiene derivatives with a partial control of stereochemistry is described from two potentially precursor enals by a judicious choice of experimental conditions (Ac 2 O/DMAP in Et 3 N). These conditions have been successfully applied in the first total synthesis of caulerpenyne.

Carboxylate‐Directed Tandem Functionalisations of α,β‐Dihaloalkenoic Acids with 1‐Alkynes: A Straightforward Access to (Z)‐Configured, α,β‐Substituted γ‐Alkylidenebutenolides

An easy and mild copper(I)-catalysed lactonisation of readily available (E)-2,3-dihalopropenoic acid derivatives regio- and stereoselectively leads to rarely described (Z)-3-halo-5-ylidene-5H-furan-2-ones. These compounds are subsequently able to undergo classical Pd-catalysed cross-coupling reactions, providing 3-substituted and 3,4-disubstituted 5-ylidene-5H-furan-2-ones

Design, synthesis and biological evaluation of a bivalent μ opiate and adenosine A1 receptor antagonist

The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A(1) adenosine and mu opiate receptors with a K(i) of 0.8+/-0.05 and 0.7+/-0.03 microM, respectively. This hybrid molecule increases cAMP production in cells that over express the mu receptor as well as those over expressing the A(1) adenosine receptor and reverses the antalgic effects of mu and A(1) adenosine receptor agonists in animals.

Dramatic influence of the substitution of alkylidene-5H-furan-2-ones in Diels–Alder cycloadditions with o-quinonedimethide as diene partner: en route to the CDEF polycyclic ring system of lactonamycin

An efficient and rapid synthesis of the CDEF ring system of lactonamycinone is reported via a highly chemo- and diastereoselective intermolecular Diels-Alder cycloaddition between trans-1,2-disilyloxybenzocyclobutene and the appropriate γ-alkylidenebutenolide. The feasibility and the total chemoselectivity of the [4 + 2] cycloaddition for the construction of a spirolactone moiety via an intramolecular approach (IMDA) using both partners is also described demonstrating the versatility of the γ-alkylidenebutenolide building block.

Expeditious synthesis and biological evaluation of new C-6 1,2,3-triazole adenosine derivatives A1 receptor antagonists or agonists

The synthesis of new C-6 1,2,3-triazole adenosine derivatives via microwave assisted 1,3-dipolar cycloaddition as key step is described. The binding on membranes of cells that over express A(1) adenosine receptors (A(1)AR) was also evaluated. Among them, four compounds increased cAMP production, in a dose-dependent manner acting as antagonists of the A(1)AR, while two compounds act as agonists.

trans-1,2-Disiloxybenzocyclobutene, an adequate partner for the auto-oxidation: EPR/spin trapping and theoretical studies

The auto-oxidation of trans-1,2-disiloxybenzocyclobutene was found to be very efficient, giving endo-peroxide in quantitative yield. Each step of the mechanism of spin-forbidden addition of triplet oxygen O2((3)Σg) was studied by both EPR/spin trapping and theoretical studies.

Caulerpenyne binding to tubulin: structural modifications by a non conventional pharmacological agent.

The most widely used molecules in cancer chemotherapy are Vinca-alkaloids and Taxoids, numerous chemists attempted the synthesis of analogs which bind to their well-known tubulin pharmacological site. Unfortunately, tumors develop resistance to these compounds; therefore the definition of anchoring points and potential binding sites for new drugs on tubulin is of major interest. Caulerpenyne (Cyn), the major secondary metabolite synthesized by the green marine alga Caulerpa taxifolia could be one of these drugs, since it inhibits the assembly of tubulin and MTP (Barbier et al., 2001). We observed that the tubulin-Cyn complex is poorly reversed. Cyn did not bind to sulfhydryl groups and the measure of the extent of binding is 1.6 +/- 0.2 suggesting two potential binding sites. Then, we demonstrated by competition measurements that Cyn did not interact to colchicine, Taxol and Vinca-alkaloid binding domain. Finally, mass spectrometric analysis of proteolytic cleavage of tubulin-Cyn complex demonstrated that Cyn did not bind covalently to tubulin and evidenced two good candidate regions for Cyn binding, one on alpha-tubulin and the other on beta-tubulin.