Reversal of the Importance of Steric and Electronic Effects in the Base-Promoted α‑Silylation of Sulfides

Lithiation of α–C-H groups in organic substrates by RLi or R₂NLi followed by silylation with R′₃SiCl generally provides analogous products regardless of the R′ group of R′₃SiCl. A striking exception using 3,4-benzothiophane as substrate depending on whether R′ is methyl, phenyl, or isopropyl is demonstrated. With R′ = Me or Ph, the geminal α,α-bis-silylated products result whereas with <i>i</i>-Pr₃SiCl the <i>trans</i>-α,α′-bis-silylated sulfide is formed. The latter pathway provides ready access to the <i>C</i>₂-symmetric enantiomers of <i>trans</i>-2,5-bis­(triisopropylsilyl)-3,4-benzothiophane

A New, Short, and Stereocontrolled Synthesis of <i>C</i>₂‑Symmetric 1,2-Diamines

The previously unknown 5-spirocyclohexylisoimidazole has been made efficiently and simply by reaction of ammonia, glyoxal hydrate, and cyclohexanone. It is a very useful precursor for the diastereocontrolled synthesis of many <i>C</i>₂-symmetric 1,2-diamines, a class which is important for the generation of a variety of <i>C</i>₂-symmetric reagents and catalysts for enantioselective synthesis

De Novo Synthesis and Biological Evaluation of C6″-Substituted C4″‑Amide Analogues of SL0101

In an effort to improve upon the <i>in vivo</i> half-life of the known ribosomal s6 kinase (RSK) inhibitor SL0101, C4″-amide/C6″-alkyl substituted analogues of SL0101 were synthesized and evaluated in cell-based assays. The analogues were prepared using a de novo asymmetric synthetic approach, which featured Pd-π-allylic catalyzed glycosylation for the introduction of a C4″-azido group. Surprisingly replacement of the C4″-acetate with a C4″-amide resulted in analogues that were no longer specific for RSK in cell-based assays

An Orally Active Phenylaminotetralin-Chemotype Serotonin 5‑HT₇ and 5‑HT_1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT₇ receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT_1A partial agonist with relevant affinity at 5-HT₇ receptors. Herein, we report the synthesis, <i>in vitro</i> molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2′-fluorophenyl)-<i>N</i>,<i>N</i>-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT₇ (<i>K</i>_i = 5.8 nM, EC₅₀ = 34 nM) and 5-HT_1A (<i>K</i>_i = 22 nM, EC₅₀ = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (<i>+</i>)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT₂ agonist, DOI. Systemic (<i>+</i>)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (<i>+</i>)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders

Improving the Affinity of SL0101 for RSK Using Structure-Based Design

Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product SL0101 (kaempferol 3-<i>O</i>-(3″,4″-di-<i>O</i>-acetyl-α-l-rhamnopyranoside)) has been shown to be an RSK selective inhibitor. However, the <i>K</i>_i for SL0101 is 1 μM with a half-life of less than 30 min <i>in vivo</i>. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5″-<i>n</i>-propyl group on the rhamnose that has >40-fold improved affinity for RSK relative to SL0101 in an <i>in vitro</i> kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5″-<i>n</i>-propyl analogue to inhibit MCF-7 proliferation was only 2-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5″-<i>n</i>-propyl analogue for RSK will aid in the design of future compounds for <i>in vivo</i> use