No abstract

The first enantioselective synthesis of (+)–isolysergol was completed in 12 steps from commercially available materials by a novel approach that features a late stage microwave-mediated, diastereomeric ring closing metathesis catalyzed by a chiral molybdenum catalyst to simultaneously form the D ring and set the stereocenter at C(8).

SYNOPSIS The eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein containing hypusine, [Nε-(4-amino-2-hydroxybutyl)lysine]. eIF5A is activated by the posttranslational synthesis of hypusine and the hypusine modification is essential for cell proliferation. In this study, we report selective acetylation of the hypusine and/or deoxyhypusine residue of eIF5A by a key polyamine catabolic enzyme, spermidine/spermine- N1-acetyltransferase 1 (SSAT1). This enzyme normally catalyzes the N1-acetylation of spermine and spermidine to form acetyl-derivatives, which in turn are degraded to lower polyamines. Although SSAT1 has been reported to exert other effects in cells by its interaction with other cellular proteins, eIF5A is the first target protein specifically acetylated by SSAT1. Hypusine or deoxyhypusine, as the free amino acid, does not act as a substrate for SSAT1, suggesting a macromolecular interaction between eIF5A and SSAT1. Indeed, the binding of eIF5A and SSAT1 was confirmed by pull-down assays. The effect of the acetylation of hypusine on eIF5A activity was assessed by comparison of acetylated vs non-acetylated bovine testis eIF5A in the methionyl-puromycin synthesis assay. The loss of eIF5A activity by this SSAT1-mediated acetylation confirms the strict structural requirement for the hypusine side chain and suggests a possible regulation of eIF5A by hypusine acetylation/deacetylation.

Oxide-bridged phenylmorphans were conceptualized as topologically distinct, structurally rigid ligands with 3-dimensional shapes that could not be appreciably modified on interaction with opioid receptors. An enantiomer of the N-phenethyl-substituted ortho-f isomer was found to have high affinity for the μ-receptor (Ki = 7 nM) and was about four times more potent than naloxone as an antagonist. In order to examine the effect of introduction of a small amount of flexibility into these molecules, we have replaced the rigid 5-membered oxide ring with a more flexible 6-membered carbon ring. Synthesis of the new N-phenethyl-substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols resulted in a two carbon-bridged relative of the f-isomers, the dihydrofuran ring was replaced by a cyclohexene ring. The carbocyclic compounds had much higher affinity and greater selectivity for the μ-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent μ-antagonists, with activities comparable to naltrexone in the [35S]GTPγS assay.