Françoise Guéritte

Application of a modification of the Polonovski reaction to the synthesis of vinblastine-type alkaloids.

Eine neue C-16/C-2 l-Fragmentierungvon Ibogan-Derivaten wie (I) oder (VI), induziert durch eine modifizierte Polonovski- Reaktion, fuhrt in Gegenwart von Aspidosperman-Derivaten wie (II) (Vindolin) zu Verbindungen vom Vinblastin-Typ mit naturlicher [(S)-] Konfiguration an C-16 [notwendig fur eine signifikante Antitumor-Aktivitat ], z.B. (IVa) (Anhydro-vinblastin) bzw. (VIIa) [daneben werden die Epimeren (IVb) bzw. (VIIb) gebildet; weiterhin konnen Produkte einer Fragmentierung am C-5 /C-6 wie (V) auftreten].

Prostratin and 12-o-tetradecanoylphorbol 13-acetate are potent and selective inhibitors of chikungunya virus replication

A chemical study of the Vietnamese plant species Trigonostemon howii led to the isolation of a new tigliane-type diterpenoid, trigowiin A (1), along with several known coumarins and phenylpropanoids. The planar structure and the relative configuration of compound 1 were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Trigowiin A (1) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Since the structure of compound 1 is closely related to those of well-known tigliane diterpenoids such as prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13-acetate (TPA) (4), and 4α-TPA (5), the antiviral activity of the latter compounds was also evaluated against CHIKV, as well as in virus-cell-based assays of two additional members of the genus Alphavirus (Sindbis virus, SINV, and Semliki forest virus, SFV). Whereas prostratin inhibited CHIKV replication with a moderate EC(50) of 2.6 μM and a selectivity index (SI) approximating 30, compound 4 proved to be an extremely potent inhibitor, with an EC(50) of ∼3 nM and a SI near 2000. Interestingly, no or very little activity was observed on the replication of SINV and SFV.

A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3′ single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNA-binding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs.

Comparative pharmacokinetics of antitumor Vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats

SummaryThe kinetics of distribution and elimination in rats of the antitumor drug navelbine and of two of its analogues, Na-formyl navelbine and deacetyl navelbine amide, have been studied by radioimmunoassay and compared with the kinetics obtained with vinblastine and vincristine. Fitting to two-exponential curves was used to derive pharmacokinetic parameters. Clearance was found to parallel toxicity for all drugs: it increases from 0.19 l h-1 kg-1 for vincristine to 0.41 for Na-formyl navelbine, 1.4 for vinblastine, 2.3 for navelbine, and 2.6 for deacetyl navelbine amide. Terminal half-lives were longer for the Naformyl-substituted alkaloids (around 13 h) than for the others (8–10 h). We have also studied navelbine kinetics in cancer patients entered in recent navelbine clinical trials and found that navelbine pharmacokinetics are characterized by fast and extensive distribution, high clearance (0.92±0.27 l h-1 kg-1), and a relatively long terminal half-life (31.2±4.4 h). Relationships between chemical structure, pharmacokinetic properties, and toxicity or therapeutic efficiency within the Vinca alkaloid series are discussed, together with the relevance of animal models such as the rat in the screening of new antitumor drugs.

Antiviral chlorinated daphnane diterpenoid orthoesters from the bark and wood of Trigonostemon cherrieri

The chemical study of the bark and the wood of Trigonostemon cherrieri, a rare endemic plant of New Caledonia, led to the isolation of a series of highly oxygenated daphnane diterpenoid orthoesters (DDO) bearing an uncommon chlorinated moiety: trigocherrins A-F and trigocherriolides A-D. Herein, we describe the isolation and structure elucidation of the DDO (trigocherrins B-F and trigocherriolides A-D). We also report the antiviral activity of trigocherrins A, B and F (1, 2 and 6) and trigocherriolides A, B and C (7-9) against various emerging pathogens: chikungunya virus (CHIKV), Sindbis virus (SINV), Semliki forest virus (SFV) and dengue virus (DENV).

Trigocherrin A, the first natural chlorinated daphnane diterpene orthoester from Trigonostemon cherrieri.

Trigocherrin A, a chlorinated and highly oxygenated daphnane diterpenoid orthoester (DDO), was isolated from the bark of Trigonostemon cherrieri. Trigocherrin A is the first example of a naturally occurring halogenated DDO. Its structure was elucidated by comprehensive analysis of NMR spectroscopic data, and its absolute configuration was determined by comparison of experimental and theoretically calculated ECD spectra. Trigocherrin A exhibited a potent and selective effect against Chikungunya virus in Vero cells.

Effects of the hydrophobicity of taxoids on their interaction with tubulin

Modifications of the hydrophobic character at the 7 and 10 positions of the taxoids greatly modified the effect of these drugs on the tubulin microtubule system. The presence of an alkyl chain at these positions decreased the activity while their corresponding more polar analogues restored the activity of these molecules. It appears that the recognition of taxoids by tubulin depends on the location of the most important hydrophobic area.

Seasonal variation of neutral and basic taxoid contents in shoots of European Yew (Taxus baccata)

Abstract Seasonal variations of taxoid constituents were determined in shoots of European Yew collected from two locations. The first samples originated from a male Taxus baccata tree growing in Gif, France. The second samples were obtained from genetically identical female Irish Yew trees ( T. baccata var. fastigiata ), of the same age and growing at one site in Dublin, Ireland. Shoots were collected monthly for one year and separated into needles and stems. Neutral taxoids (paclitaxel and 10-deacetylbaccatin III (10-DAB III)) and basic taxoids (including taxines B) were extracted and quantified. Needles yielded significantly higher levels of taxoids than stems. 10-DAB III contents in needles of French samples showed considerable monthly fluctuations, while in needles of the Irish samples maximum yields of 10-DAB III were found in June. Highest levels of paclitaxel were present between February and April. Basic taxoids occurred in highest concentrations (total alkaloids 9.49 g/kg) in the August collection of French samples, but in needles of the Irish Yew in November and December (total alkaloids 16.9 g/kg; taxines B 10.9 g/kg). No conclusion could be drawn as to the optimum time of year for harvesting, since this varies from tree to tree, depending on T. baccata variety, location and taxoid type.

Partial synthesis of vinblastine-type alkaloids

Application of a modification of Polonovskis reaction facilitates partial synthesis of vinblastine-type alkaloids.

4-Phenylcoumarins from Mesua elegans with acetylcholinesterase inhibitory activity

A significant acetylcholinesterase (AChE) inhibitory activity was observed for the hexane extract from the bark of Mesua elegans (Clusiaceae). Thus, the hexane extract was subjected to chemical investigation, which led to the isolation of nine 4-phenylcoumarins, in which three are new; mesuagenin A (1), mesuagenin C (3), mesuagenin D (4) and one new natural product; mesuagenin B (2). The structures of the isolated compounds were characterized by spectroscopic data interpretation, especially 1D and 2D NMR. Four compounds showed significant AChE inhibitory activity, with mesuagenin B (2) being the most potent (IC(50)=0.7μM).