Wayne M. Best

The synthesis of some epoxyalkyl Beta-C-Glycosides as potential inhibitors of Beta-Glucan hydrolases

The treatment of tetra-O-benzyl-D-glucono-1,5-lactone with various alkenylmagnesium halides gave the intermediate lactols which, upon reduction (Et3SiH/BF3) and protecting group manipulation, yielded alkenyl tetra-O-acetyl-beta-D-C-glucopyranosides in good yield. These beta-D-C-glucosides were precursors of the epoxyalkyl beta-D-G-glucopyranosides, themselves putative inhibitors of beta-glucan hydrolases. Similar additions of Grignard reagents to per-benzylated cellobionolactone were not as successful in yielding epoxyalkyl beta-C-cellobiosides. The addition of Grignard reagents to 1,2-anhydro-3,4,6-tri-O-benzyl-alpha-D-glucose offers a viable alternative route to the prop-2-enyl beta-D-C-glucoside, but not to the but-3-enyl and pent-4-enyl counterparts. Likewise, the addition of Grignard reagents to a 1,2-anhydro cellobiose gave disappointing results. Preliminary results are reported for a novel approach to alkenyl beta-D-C-glucosides by the alkylation of nitromethyl beta-D-C-glucosides.

Palladium-Catalysed Cross Coupling of Arylboronic Acids with 2-Chloro-1,4-naphthoquinones: the Synthesis of 2-Aryl- and 2,3-Bisaryl-1,4-naphthoquinones

2-Chloro-1,4-naphthoquinones underwent palladium-catalysed cross coupling reactions with arylboronic acids to give the corresponding 2-aryl-1,4-naphthoquinones. Similarly, 2,3-dichloro-1,4-naphthoquinone underwent efficient cross coupling reactions with arylboronic acids to give mono or bis adducts. The required 2-chloro-1,4-naphthoquinones were conveniently prepared from the corresponding 2-hydroxy-1,4-naphthoquinones by treatment with oxalyl chloride.

The intracellular and nuclear‐targeted delivery of an antiandrogen drug by carrier peptides

Cell permeable carrier peptides are currently of interest for their potential to improve the delivery of bioactive molecules into cells and to specific cellular compartments. We have investigated the activity of a derivative of the antiandrogen drug, bicalutamide, attached to the cell-permeable carrier peptide penetratin(R). We have used both disulfide (labile) and thioether (nonlabile) linkages to attach the bicalutamide derivative to the peptide in order to assess whether one type of chemistry has advantages over the other. In addition we have added a nuclear localization sequence (NLS) to the carrier peptide to investigate whether localization of the drug to the nucleus of the cell affects the activity of the drug. Biotin-labeled peptides were used to demonstrate that the carrier peptide is rapidly accumulated inside cultured cells, and that the incorporation of an NLS in the sequence results in its nuclear targeting. The bicalutamide derivative linked to carrier peptides via a disulfide-linkage exerted no greater antiproliferative effect in LNCaP cells, than the bicalutamide derivative alone. The bicalutamide derivative linked to the carrier peptide by a non-labile thioether linkage showed a similar activity profile. When the construct includes a nuclear targeting sequence, however, a markedly increased antiproliferative effect was observed. This study has thus shown that the activity of bicalutamide may be enhanced by the nonlabile attachment of a cell-permeable and nuclear-targeted peptide, which has implications for the development of novel antiandrogens for the treatment of prostate cancer.

Simple Synthesis of Symmetrical 4-Substituted 3,5-Dialkylisoxazoles

A number of symmetrical 4-substituted 3,5-dialkylisoxazoles have been prepared by treatment of aromatic aldehydes with nitroalkanes and aqueous sodium hydroxide.