Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional “slow release” concept.     

Tetra-acetylenic metabolites from Mycena viridimarginata

The structures of two new acetylenic compounds from Mycena viridimarginata were elucidated by spectroscopic methods and some chemical transformations. The major metabolite was 10-hydroxyundeca-2,4,6,8-tetraynamide and the minor one was 3,4,13-trihydroxytetradeca-5,7,9,11-tetraynoic acid γ-lactone. Another compound, methyl-3,4,13-trihydroxytetradeca-5,7,9,11-tetraynoate, was found to be an artifact from the γ-lactone produced on the Sephadex LH-20 column. Furthermore, model compounds were prepared to establish the chromophoric system of the major metabolite.     

Metabolites from endophytes of the medicinal plant Erythrina crista-galli

Erythrina crista-galli (Fabaceae) is used in Argentinean ethnopharmacology as anti-inflammatory medication, narcotic, desinfectant, and for the treatment of wounds. The common name of the tree is "ceibo" or coral tree. The dominating endophytes in E. crista-galli all belong to the genus Phomopsis as identified by microscopic features and the analysis of their ITS sequences. To investigate a possible contribution of Phomopsis spp. to the metabolites found in the plant, twelve different isolates were cultivated in different media. Besides several new metabolites a number of known compounds were detected: mellein, nectriapyrone, 4-hydroxymellein, scytalone, tyrosol, clavatol, mevinic acid, and mevalonolactone.