Daniel Guenard

Application of the vicinal oxyamination reaction with asymmetric induction to the hemisynthesis of taxol and analogues

Abstract Taxol, 10-deacetyl taxol and their related side chain analogues can be obtained via a “Sharpless” oxyamination reaction on 13-cinnamoyl baccatin III. Asymmetric induction has been studied using different bridgehead amines as chiral ligands. This procedure constitutes an alternative route to taxol derivatives for biological studies.

Chemical studies of 10-deacetyl baccatin III: Hemisynthesis of taxol derivatives

Abstract The chemical reactivities of 10-deacetyl baccatin III and of baccatin III, two natural products extracted from Taxus baccata L., were studied with the aim of synthesizing taxol analogues having a modified side-chain at C-13, thereby restoring good binding to tubulin.

Conformation of Taxotere® and analogues determined by NMR spectroscopy and molecular modeling studies

Abstract Taxol 1 and Taxotere® 2 are antitumor compounds interacting with tubulin proteins. In order to find the best conformational fit to the receptor site, the structures of taxotere and twelve analogues showing various in vitro biological activity on tubulin, have been investigated by 1H NMR spectroscopy and molecular modeling studies. These structures were compared to that of Taxotere® 2 obtained by X-ray analysis. The results obtained from these studies suggest that the most active 2′R,3′S compounds possess a conformation in which the benzoate group at C-2 holds the side chain in a defined position due to hydrophobic interactions between this group and the N-amido or N-carbonyloxy group at C-3′. This situation together with the presence of hydrogen bonding between 2′OH-3′NH and 2′OH-1′CO gives rise to a specific orientation of the hydroxyl and phenyl groups at C-2′ and C-3′. On the other hand, the 2′S,3′R isomers which display low in vitro biological activity (ie: on tubulin), such as isotaxotere 8, possess a different conformation with no hydrophobic interactions between the side chain and the taxan skeleton.

Rearrangement reactions of taxanes: structural modifications of 10-deacetylbaccatin III.

Abstract 10-Deacetylbaccatin III 2 is a taxane diterpenoid isolated from the plant genus Taxus , which has been used for the partial sythesis of the antitumor compounds taxol and taxotere®. A number of structural modifications have been performed on 2 under acidic and basic conditions in order to obtain new synthetic precursors of taxol and taxotere® analogues.

Novel B-ring modified allocolchicinoids of the NCME series: design, synthesis, antimicrotubule activity and cytotoxicity

Two new series of allocolchicinoids mimicking the structure of (-)-N-acetylcolchinol O-methyl ether (2, NCME) were synthesized and evaluated for their abilities to inhibit tubulin assembly. Possible antitumor properties resulting thereof were evaluated in vitro on the human MCF-7 breast cancer cell line. The first series of NCME-derivatives was brought about by extending the seven membered B-ring to novel semisynthetic variations with a nitrogen containing eight-membered B-ring similar, for example, to the artificial, potent steganacin aza-analogue 3. In the second series the seven-membered B-ring of NCME (2) was modified by annulation with a heterocyclic ring system. The racemic ketone 7a serving as key precursor involved in the syntheses of all the target NCME variants 9-13 and 15, 16 was easily transformed into the eight-membered B-ring lactams 9 and 10 via a Beckmann rearrangement of the corresponding E-oxime 8. The tetrazole annulated congener 11 was prepared via azidotrimethylsilane-mediated Schmidt rearrangement. Treatment of educt 7a with Brederecks reagent led to the enamino ketone 14, which was easily converted into the pyrazole- or pyrimidine-annulated allocolchicinoids 15 and 16. Remarkably, all the allocolchicinoids 9-13 with an azocin-B-ring affected the tubulin/microtubule equilibrium only moderately. In contrast, the novel heterocycle annulated seven membered B-ring variants 15 and 16 proved to be highly potent tubulin-inhibitory, antimitotic agents. Interaction with tubulin occured at concentrations similar to those observed for colchicine (1) or the lead NCME (2). In all cases the antiproliferative effects correlated roughly with the inhibition of tubulin assembly.

Hemisynthesis of rhazinilam analogues: structure - activity relationships on tubulin-microtubule system

Abstract Semi-synthesis of derivatives of rhazinilam, an antitubulin compound, delineated some molecular features necessary for biological activity. In the course of this study, the formation of rhazinilam from 1,2-didehydroaspidospermidine is reexamined and a new mechanism is proposed.

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.

Synthesis and biological evaluation of A-ring biaryl-carbamate analogues of rhazinilam.

An improvement of the synthesis of biphenyl-carbamate 2a, the most active analogue of rhazinilam 1 so far, was performed using the Pd-catalyzed borylation/Suzuki coupling (BSC) method developed in our laboratories. The preparation of A-ring analogues of 2a bearing electron-withdrawing or donating groups is reported according to this new synthetic scheme. The antitubulin properties as well as the cytotoxicity of these compounds toward human cancer cell lines were evaluated in comparison with rhazinilam and 2a.

Absence of 7-acetyl taxol binding to unassembled brain tubulin

The effect of taxol on microtubule proteins at 0°C is controversial. In order to determine if taxol is unable to bind to unassembled tubulin, as has been hypothesized, the binding of [3H]acetyl taxol has been studied using equilibrium microdialysis. Ac‐taxol bound to microtubules at 37°C and the binding remained stable when the temperature was lowered to 0°C. Ac‐taxol bound also at 0°C to microtubules stabilized with rhazinilam. In contrast, there was no binding of Ac‐taxol to unassembled tubulin, either free tubulin at 0°C or tubulin, complexed with several microtubule poisons, at 0 and 37°C.