ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Boron Compounds/chemical synthesis , Putrescine/analogs & derivatives , Putrescine/chemical synthesis , Spermidine/analogs & derivatives , Spermidine/chemical synthesis , Animals , Biological Transport, Active , Boron Compounds/metabolism , Boron Neutron Capture Therapy , Cell Line , DNA/chemistry , Putrescine/metabolism , Spermidine/metabolism , Spermine/analogs & derivatives , Structure-Activity Relationship , Tomography, Emission-Computed , Tumor Cells, CulturedABSTRACT
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.
ABSTRACT
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).