Girolline interferes with cell-cycle progression, but not with translation

Girolline is a 2-aminoimidazole derivative with cytotoxic activity. It affects the survival of exponentially growing leukaemic cultured cells and has a significant antitumour activity on grafted murine tumours in vivo. In vitro studies showed that girolline affected protein synthesis by interfering with the translation termination process. Here, we investigate the effect of girolline on translation termination in human cultured cells. We show that girolline neither induces an increase in translational readthrough of stop codons nor affects the polysome profile in treated cells. This suggests that girolline does not act on translation in vivo. Then, we examine the effect of girolline on cell-cycle progression and we show that girolline induces an arrest of the cell cycle at the G2 stage

Synthèse de taxoïdes à cycle D thiétanique à partir des taxines B (synthèse d'un isostère de la girolline)

La première partie de ce mémoire décrit l'hémisynthèse d'un analogue du Taxol(R), le 7-désoxy-10-acétyl-5(20)- désoxy-5(20)-sulfanyldocétaxel, qui possède un atome de soufre dans le cycle D à la place de l'oxygène. Les taxines B isolées des feuilles de l'if constituent la matière première de cette hémisynthèse. Dans un premier temps le cycle D thiétanique a été construit, sur un produit protégé en position 9,10, par ouverture d'un époxyde en position 4,20 par un thioacétate formé in situ, puis action d'une base qui permet la cyclisation en thiétane par déplacement d'un groupe partant en position 5. L'acétylation de l'hydroxyle en position 4 se révèle alors difficile à réaliser, et la déprotection en 9,10 impossible. Dans un deuxième temps, la synthèse est réalisée sur un composé possédant les fonctions voulues en 9,10 dès le début de la synthèse. De plus le problème de l'acétylation de l'hydroxyle en 4 est résolu en utilisant le thioacétate de potassium, ce qui permet de réaliser la cyclisation en thiétane et l'acétylation en une seule étape...The first part of the thesis deals with the semisynthesis of Taxol(R) analogue, the 7-deoxy-10-acetyl-5(20)- deoxy-5(20)-sulfanyldocetaxel, in which the oxygen atom of the D-ring is replaced by a sulfur atom. The starting material is the mixture of taxines B extracted from the leaves of the European yew tree Taxus baccata L. At first, the thietane ring formation is realized on a 9,10 protected compound. A derivative doubly substituted by a leaving group (a mesylate on the C-5) and a thioacetate group (introduced by opening a 4.20 epoxide) is prepared and the mesylate undergoes an intramolecular nucleophilic substitution by an in situ sulfide. The acetylation of the C-4 hydroxyl group can be done only with poor yield and the cleavage of the 9,10 protecting group is impossible. Then, the synthesis starts from a taxine derivative that contained suitable fonctions at positions 9,10. Cyclisation in thietane is with concomitant acetylation of the C-4 hydroxyle obtained by using potassium thioacetate. The final product is cytotoxic but inactive on microtubule disassembly. The second part of this work deals with attempts to synthesize two analogues of the girolline (two diastereoisomers)...ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

NOUVEAU DERIVE DE LA 7-DESACETOXY BACCATINE IV, SA PREPARATION ET SON EMPLOI

A novel 7-deacetoxy baccatine IV derivative having formula (I), the preparation thereof from taxine B, and its use in preparing biologically active products, are described. In said formula (I), R is a hydrogen atom or acetyl radical and R1, R2, R3, and R4 are hydroxy-function protective groupings (preferably acetonides)

NOUVEAU DERIVE DE LA 7-DESACETOXY BACCATINE IV, SA PREPARATION ET SON EMPLOI

A novel 7-deacetoxy baccatine IV derivative having formula (I), the preparation thereof from taxine B, and its use in preparing biologically active products, are described. In said formula (I), R is a hydrogen atom or acetyl radical and R1, R2, R3, and R4 are hydroxy-function protective groupings (preferably acetonides)

Plantes de Nouvelle-Calédonie.114. Taxanes isolés des feuilles d'Austrotaxus spicata Compton (Taxacées)

International audienc

Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloid lunarine and related natural products

The macrocyclic spermidine alkaloid lunarine 1 from Lunaria biennis is a competitive, time-dependent inhibitor of the protozoan oxidoreductase trypanothione reductase (TryR), a promising target in drug design against tropical parasitic diseases. Various molecules related to I and the alkaloid itself have been synthesized in racemic form and evaluated against TryR in order to determine the key features of I that are associated with time-dependent inhibition. Kinetic data are consistent with an inactivation mechanism involving a conjugate addition of an active site cysteine residue onto the C-24-C-25 double bond of the tricyclic nucleus of 1. Comparison of data for synthetic (+/-)-1, the natural product, and other derivatives 7-10 from L. biennis confirms the importance of the unique structure of the tricyclic core as a motif for inhibitor design and reveals that the non-natural enantiomer may be a more suitable scaffold upon which thiophilic groups may be presented. (c) 2005 Elsevier Ltd. All rights reserved

Homophymines B-E and A1-E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp.

Nine new cyclodepsipeptides, homophymines B–E (2–5) and A1–E1 (1a–5a), were isolated from the polar extracts of the sponge Homophymia sp. The new structures, featuring new polyketide-derived end groups, were determined by interpretation of NMR and MS data. The configurations of the new end groups was secured by the application of J-based configurational analysis. Homophymines displayed very potent antiproliferative activity (IC50 in the nM range) against a panel of human cancer cell lines