Pierre Blanchard

Inhibition of virus-induced cell transformation by synthetic analogues of S-adenosyl homocysteine

Summary 1 mM 5′-deoxy-5′-S-isobutyl-adenosine (SIBA) (I), a structural analogue of S-adenosyl-homocysteine (SAH), inhibits the oncogenic transformation of chick embryo fibroblasts (CEF) infected with Rous sarcoma virus (RSV). When SIBA remains in contact with infected cells for 48 hours the inhibition of focus formation is irreversible, at least for 8 days. Virus replication is also strongly inhibited by SIBA. Normal CEF are only reversibly inhibited by this compound. SAH, the natural inhibitor of SAM dependent transmethylases has no effect on cell transformation.

A mild and effective iodination method using iodine in the presence of bis-(trifluoroacetoxy)iodobenzene

Abstract Herein is described a mild and effective iodination method using bis-(trifluoroacetoxy)iodobenzene-iodine as reagent to be applied to electron deficient heterocyclic systems (protected indoles, coumarin…) Moreover, sensitive protecting groups such as acetyl and tert-butyldimethylsilyl were found to be stable under the new iodination reaction conditions.

Studies on synthetic inhibitors of t-RNA methyl transferases: analogs of S-adenosyl homocysteine

Summary The structural analogs ( 1–10 ) of S-adenosyl homocysteine have been tested as inhibitors of a N-2 guanine methyltransferase and a whole methyltransferase extract, both isolated from rabbit liver with E. coli B and E. coli K 12 f met t-RNAs as substrates. Derivatives in which the amino function of the adenyl moiety had been completely substituted (SAH f) 9 or replaced by an hydroxyl (SIH) 10 were devoid of inhibitory activity. However, if one hydrogen atom was still linked to the N-6 atom, (N 6 methyl SAH 8 ), the product was still an efficient competitive inhibitor (Ki 60 moles). A chiral change or the replacement of the homocysteine chain by different analogs such as thio ethanol 4 , thio propanediol 6 , thio propionic acid 5 or D homocysteine 1c , led to products displaying inhibitory activity on the methyltransferases. For instance D SAH 1c was found to be a potent competitive inhibitor of the reaction (Ki 40 moles). The comparison of the inhibition values obtained with SAC 2, SA cysteamine 3 , SAEtOH 4 and SA propionic 5 suggests an important hydrogen type bond between the terminal amino function and the enzyme whereas the terminal carboxyl group did not contribute efficiently to the binding of the inhibitors to the enzyme.

A conjugate addition of primary alkyl iodide derived species to electron deficient olefins

Abstract Efficient zinc/copper couple induced addition of carbohydrate or amino acid residues derived from their corresponding iodides to various activated olefins have been accomplished by simple vibromixing of the heterogenous reaction mixture.

Zinc-copper couple promoted C-branching in the carbohydrate series

Abstract Efficient C-branching at 3-position of di-O-isopropylidene glucose was readily accomplished by the zinc/copper couple induced conjugate addition of its 3-iodo derivative to various activated olefins at room temperature in a protic solvent mixture.

Synthesis of adenine nucleosides related to sinefungin

Abstract The extended adenine nucleosides 2a-b and 3 have been prepared from D-ribose by a reasonably short sequence using the suitably functionalized intermediate 6 .

Synthesis and Biological Activities of Some New 5′-Substituted S-Adenosylhomocysteine Analogues∗

Abstract The synthesis of new S-adenosyl-homocysteine (SAH) analogues substituted at the 5′-position is described. Their activity on cell transformation induced by Rous sarcoma virus (RSV) as well as their effect on cell growth and on replication of polyoma virus were also studied. The best results were obtained with compounds having a phenyl group at the 5′-position of adenosine. These molecules inhibit very strongly uridine uptake by cells.

A SYNTHETIC APPROACH TO CARBOCYCLIC SINEFUNGIN

Abstract An approach to an asymmetric synthesis of carbocyclic sinefungin (cSF) 2 is proposed. The sequence, which uses an original radical based chemistry for C-C bond formation, led to the immediate precursor 18 of the protected desired compound. While the overall yield is modest, it is noticeable that only a limited number of steps are needed to obtain the target compound.

Relationship Between Chemical Structure and Antileishmanial Effect of Sinefungine Analogues

Abstract The synthesis of various analogues of sinefungin (l), having structures 2-5, has been developed by means of an original approach which uses radical chemistry. The study of their biological activities revealed that for the antileishmanial effect of sinefungin, the presence of the amino group at C-6′ in the (S)-configuration and the presence of the carboxyl group at C-9′ are necessary.

Comparative effect of methioninyl adenylate on the growth of Salmonella typhimurium and Pseudomonas aeruginosa

The bacteriostatic effect of methioninyl adenylate (MAMP)—a specific inhibitor of the enzyme methionyl-tRNA synthetase—was investigated on Salmonella typhimurium and Pseudomonas aeruginosa.0.1 mM of this molecule added to the culture, inhibits the growth of S. typhimurium. The inhibition is specifically reversible by 0.1 mM L-methionine. In the same conditions even 1–2 mM MAMP has a very slight effect on the growth rate of P. aeruginosa and only during the first two generations. The same observation was made with the two other members of the fluorescens group P. fluorescens and P. putida.The growth rate of P. testosteroni with 1 mM MAMP in the medium is similar to the growth rate of P. aeruginosa but the other member of the acidovorans group P. acidovorans is much more affected by the same concentration of the inhibitor. — P. multivorans is inhibited by MAMP like P. acidovorans but with a somewhat higher yield at the end of the culture.—MAMP has no effect on P. alcaligenes.The possible reasons for the weak bacteriostatic effect of MAMP on P. aeruginosa were investigated. It was established that the inhibitor enters the cells and is not used as a carbon and energy source. The intracellular methionine concentration in S. typhimurium and in P. aeruginosa is about the same and does not increase when bacteria are cultivated with MAMP. The MTS of the two microorganisms is inhibited by MAMP in vitro to about the same extent. Furthermore the tRNAmet from P. aeruginosa are fully acylated after 3 to 4 generations with this compound. Nevertheless MAMP elicits higher MTS activity in P. aeruginosa and in P. acidovorans after 1 h of incubation. The most striking difference between S. typhimurium and P. aeruginosa is that the intra and extracellular level of 5′phosphodiesterase which degrades MAMP is 10–20 fold higher in the second than in the first species.