Identification of multiple 5-HT₄ partial agonist clinical candidates for the treatment of Alzheimer's disease.

The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists.

Total synthesis of mycalamide A.

This communication describes a concise and efficient total synthesis of mycalamide A by the convergent coupling of pederic acid unit with the mycalamine unit. The left-half, (+)-7-benzoylpederic acid, was synthesized from (2R,3R)-3-methylpent-4-en-2-ol in seven steps and 34.6% overall yield through a route that features a one-step Pd(II)-catalyzed tandem Wacker/Heck cyclization reaction to prepare the tetrahydropyran ring system.

A general strategy to elisabethane diterpenes: stereocontrolled synthesis of elisapterosin B via oxidative cyclization of an elisabethin precursor.

Described is an efficient synthesis of the complex bioactive natural product, elisapterosin B, a potent in vitro inhibitor of Mycobacterium tuberculosis H37Rb. The synthesis elisapterosin B, prepared in its enantiomeric form, proceeds by a highly stereocontrolled sequence commencing with a simple glutamic acid derived compound. Pivotal steps in the sequence include (a) a pinacol-type ketal rearrangement to transfer chirality, (b) an IMDA reaction of an E,Z-diene to construct the elisabethin skeleton, and (c) a biosynthesis-inspired oxidative cyclization of the elisabethin precursor to elisapterosin B.

Estrogen receptor binding assay method for endocrine disruptors using fluorescence polarization.

A rapid, simple and nonhazardous assay method for endcrine disruptors was developed using an estrogen receptor (ER) and fluorescence polarization (FP). Among the fluorescent compounds, the 17alpha-fluorescein-labeled estradiol derivative was selected as the most suitable ligand for the ER binding assay, since it showed the highest affinity to ER. In the Scatchard plot analysis, its convex curve exhibited a positive cooperative binding, indicating the induction of a conformational change of the ER with the binding of the ligand to form a dimer and to increase the affinity for the additional ligand.