Asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones involving a key allylboration step. First access to (-)-nicotlactone B and (-)-galbacin.

An efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an advanced intermediate towards the first synthesis of natural products, (-)-nicotlactone B and (-)-galbacin, have thus been obtained.

N-Benzylpolyamines as vectors of boron and fluorine for cancer therapy and imaging: synthesis and biological evaluation.

Cancer cells have high-affinity polyamine uptake systems with a low stringency for structural features. Putrescine, spermidine, and spermine have, therefore, been considered as potential vectors for the selective accumulation in tumors of therapeutically or diagnostically useful structures and elements. We envisaged N-benzyl derivatives of the polyamines as vectors of (10)B and (18)F for boron neutron capture therapy (BNCT) and tumor imaging by positron emission tomography (PET), respectively. In the present work, the synthesis, transport characteristics, DNA-binding properties, and cytotoxicity of several N-benzyl derivatives of putrescine and spermidine are described. The fluorinated spermidine derivative N-(3-[(4-aminobutyl)amino]propyl)[(4-fluorophenyl)methyl]amine (N(1)-4-Fbz-spd) may be useful for PET because of its high accumulation in cancer cells via the polyamine transport system. Among the boron-containing benzyl polyamines, N-(4-aminobutyl)([4-(dihydroxyboryl)phenyl]methyl)amine (4-Bbz-put) and N-(3-[(4-aminobutyl)amino]propyl)([4-(dihydroxyboryl)phenyl]methyl)amine (N(1)-4-Bbz-spd) should be suitable for BNCT, because their accumulation in B16 melanoma cells was more efficient than that of borocaptate and borophenylalanine, two reference compounds used in BNCT.

Modeling the 1,3-dipolar cycloaddition of nitrones to vinylboranes in competition with boration, cyclization, and oxidation reactions.

Structures and energetics of reactants, reactant complexes, concerted transition structures, and products of the cycloaddition of the prototypical nitrone with vinylborane have been produced and discussed. Structure optimizations have been performed at the B3LYP/6-31G(d) and B3LYP/AUG-cc-pVDZ levels of approximation, and single-point calculations on the B3LYP geometries have been carried out at the MP4(SDTQ) level with the same basis sets. Kinetic contributions to standard enthalpies, entropies, and free enthalpies have been computed at the same levels of geometry optimizations. The effects of methyl and chloro substitution on the BH2 group and of methyl substitution on the vinyl moiety has been also explicitly considered. The most striking theoretical features of this cycloaddition are (i) the formation of reactant complexes where the nitrone oxygen is strictly bound up to the boron atom (B...O interactions), (ii) their persistence in the endo/exo transition structures, and (iii) energy profiles suggesting very high reaction rates, regiospecificity (5-borylisoxazolidines) and complete endo-stereoselectivity. The BH2 (BX2) substituent appears to induce a sort of intramolecular catalysis which is also largely selective in favor of the endo reaction path. Possible competitive reaction paths such as cyclization, organoboration, and oxidation have equally been investigated, on the same grounds, both with prototypical reagents and with dimethylvinylborane, dichlorovinylborane, 2-methyl-1-propenylborane, and 2-methyl-1-propenyldichloroborane. The transition structures for these reaction paths are significantly higher in energy than those of the corresponding 1,3-dipolar cycloadditions in the sequence oxidation >> cyclization > boration > cycloaddition, whereas the resulting reaction products show the reversed sequence. Polar solvents appear to increase the competition of boration although maintaining its character of secondary reaction. As expected, the reaction rate of 1,3-dipolar cycloaddition is lowered by dimethyl substitution on the vinyl CH2 reacting center (i.e., for the reaction of 2-methyl-1-propenylborane and 2-methyl-1-propenyldichloroborane) whereas the reaction rate of boration is increased, the boration results being significantly competitive even in the gas phase. Experiments for the control of the above predictions are not yet available.

Metal-catalyzed release of supported boronic acids for C-C bond formation.

The viability of solid-supported boronic acids as reagents for Suzuki couplings and nucleophilic additions to aldehydes and enones was successfully demonstrated. This metal-catalyzed cleavage strategy allows the synthesis of a series of functionalized biphenyl products, benzylic alcohols, and beta-substituted ketones.

Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 2. Structural modifications of the spermidine moiety.

A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene alpha to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.

Toxicity and osmoprotective activities of analogues of glycine betaine obtained by solid phase organic synthesis towards Sinorhizobium meliloti.

Seven analogues of the bacterial osmoprotectant glycine betaine (GB, trimethylammonioacetate), in which the methyl groups of the Me3N+ moiety are replaced by various substituents, were obtained by SPOS using Wang resin. Their biological activities (osmoprotection vs toxicity), appeared closely related to their uptake efficiency and their catabolism in the betaine-demethylating model bacterium Sinorhizobium meliloti.

Solid phase organic synthesis of polyamine derivatives and initial biological evaluation of their antitumoral activity.

A series of N1-monosubstituted putrescine and spermine derivatives was synthesised using a solid phase methodology. We evaluated their cytotoxicity, calmodulin antagonism and polyamine uptake inhibition, pharmacological properties shared by some antitumoral agents.

Synthesis of boronic acid analogs of L-arginine as alternate substrates or inhibitors of nitric oxide synthase.

The asymmetric synthesis of an unprotected alpha-amino boronic acid analog of L-arginine 1a (boroarg-OH. 2 HCl) and its N alpha-acetyl derivative 1b (Ac-boroarg-OH. HCl) is described. These compounds were evaluated as substrates and inhibitors of recombinant nitric oxide synthases (NOS). Boroarg-OH 1a selectively inhibited inducible NOS (IC50 = 50 microM) compared to the neuronal isoform (IC50 = 300 microM).