Pierre Potier

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].

Sponge's Molecular Diversity Through the Ambivalent Reactivity of 2-Aminoimidazole: A Universal Chemical Pathway to the Oroidin-Based Pyrrole-Imidazole Alkaloids and Their Palau'amine Congeners

The plausible biogenetic mechanism proposed in this communication clarifies the chemical pathway leading to over 60 polycyclic pyrrole-imidazole marine alkaloids isolated from more than 20 different species of various genera (Agelas, Hymeniacidon, Axinella, Acanthella, Cymbastella, Phakellia...) of sponges. The tautomerism and ambivalent reactivity of 2-aminoimidazole precursors provide a consistent chemical pathway explaining the intriguing formation of all the compounds of this class. The mechanistic proposal proposed here for the first time is unique in the sense that the chemical pathway is universal and therefore provides fertile intellectual ground for the study of the enzymatic mechanism involved in this system.

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.

Manipulation of the cabboxyl groups of α-amino-acids and peptides using radical chemistry based on esters of N-hydroxy-2-thiopyridone

Abstract Photolysis of α-amino-acid or peptide esters derived from N -hydroxy-2-thiopyridone in the presence of t -butylthiol affords the expected decarboxylation products in good yield. The reaction can be applied to the α-carboxyl or to the side chain carboxyl of glutamic and aspartic acids and thus permits the preparation of a number of useful synthons. Photolysis of side chain esters in the presence of a suitable halogen atom transfer reagent gives halides often in good yield and, especially in the case of aspartic acid derivatives, without racemisation.

The free radical chemistry of carboxylic esters of 2-selenopyridine-N-oxide: a convenient synthesis of (L)-vinylglycine

Abstract Optically pure (L)-vinylglycine has been synthesised by two different methods. The first of these involves protected (L)-glutamate esters of N -hydroxy-2-seleno-pyridine. Such esters are shown to undergo the same decarboxylotive rearrangement as their thio-analogues. Oxidative elimination of the selenopyridine residue with ozone, and with the aid of hex-1-ene as sacrificial olefin for the work-up, gave the desired (L)-vinylglycine derivatives. Similarly, the modified Hunsdiecker reaction on the terminal carboxyl of suitably protected (L)-glutamic derivatives gave the nor-bromide which readily afforded the corresponding phenylselenides on treatment with phenylselenide anion. The sequence was then as above. Using the methyl ester with corbobenzyloxy protection for the amino-function an overall yield of crystalline optically pure (L)-vinylglycine of about 45% was obtained by either route.

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.

NO, thiols and disulfides

The chemical nature of the messenger molecule, nitric oxide (NO), and especially its reactivity towards thiol groups and disuifides, could explain, at least partly, its intervention in so many different biological processes. NO can be regarded as the smallest molecule suitable for electron transport in biological systems. The S‐nitrosation reaction and its reverse reaction represent the most convenient general way to store, to transport and finally to release NO. Nitric oxide is also particularly convenient for playing a role in interconversions of thiol groups and disulfides in chain radical or oxidation‐reduction processes, and to be subsequently engaged in complex sequences of reactions accounting for different biological situations.

Methyl-β-carboline-induced convulsions are antagonized by Ro 15-1788 and by propyl-β-carboline

Abstract Injected i.v. into baboons, Ro 15-1788 (a benzodiazepine antagonist) and propyl-β-carboline-3-carboxylate did not modify either the behavior or the electroencephalogram at doses up to 2 mg/kg. Methyl-β-carboline-3-carboxylate is a potent convulsant at doses of 20 μg/kg in photosensitive baboons and 100 μg/kg in non-photosensitive baboons. These convulsive doses of methyl-β-carboline-3-carboxylate are effectively antagonized by 0.5 mg/kg of Ro 15-1788 and also by 2 mg/kg of propyl-β-carboline-3-carboxylate.

A novel approach to the synthesis of optically pure non protein α-amino acids in both L and D configurations from L-serine

Abstract Efficient syntheses of (2R)-2-Boc-amino-3-phenylsulfonyl-l-propanol 3 and its enantiomer 9 from L-serine are described. The potential of these compounds in a novel general method for the synthesis of optically pure non protein α-amino acids in both the L and D configurations is exemplified by the preparation of N-Boc-L-and D-homophenylalanine, -norvaline and -norleucine.