Futoshi Hasegawa

Stereocontrolled Synthesis of Substituted Chiral Piperidines viaOne-Pot Asymmetric 6π-Azaelectrocyclization: Asymmetric Syntheses of(−)-Dendroprimine, (+)-7-Epidendroprimine, (+)-5-Epidendroprimine, and (+)-5,7-Epidendroprimine

The asymmetric one-pot 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (-)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminoacetal compounds, resulting from the four-bond formation accompanying by controlling the stereochemistry at the two asymmetric centers. The produced cyclic aminoacetals can be regarded as synthetic precursors of substituted chiral piperidines, and the syntheses of 2,4- and 2,4,6-substituted piperidines were realized from the obtained aminoacetals by the stereoselective hydrogenation of the double bond conjugated with the C-4 ester group and alkylation at the aminoacetal moiety. In addition, the stereoselective synthesis of an indolizidine alkaloid, (-)-dendroprimine, and its three stereoisomers, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine, were achieved.

Maitotoxin-photoactive probe binds to membrane proteins in blood cells

- The photoactive and biotinylating ligand was prepared from MTX and maleimide-conjugated Hatanaka reagent with use of Diels-Alder reaction. Blood cells were subjected to affinity labelling experiments using the ligand thus obtained. The labelled band on SDS-PAGE was replaced not by MTX but by brevetoxin B (PbTx2), which suggested the presence of binding proteins in blood cells. Screening of polyether compounds for MTX inhibitory activity using Ca 2+ flux assays in C6 cells disclosed that a synthetic fragment of the hydrophilic portion of MTX inhibited the MTX activity.

Artificial ladder-shaped polyethers that inhibit maitotoxin-induced Ca2+ influx in rat glioma C6 cells

Maitotoxin (MTX) is a ladder-shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca(2+) into cells. An artificial ladder-shaped polyether possessing a 6/7/6/6/7/6/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-induced Ca(2+) influx that has ever been reported.

Stable C–N axial chirality in 1-aryluracil scaffold and differences in in vitro metabolic clearance between atropisomers of PDE4 inhibitor

We report herein the stable C-N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C-N axially chiral biaryls. In addition, there was a good correlation between the rotational barriers and van der Waals radii of an ortho-substituent of the N(1)-phenyl group. To explore the possibility of the chiral 1-phenyl-6-aminouracil scaffold as a drug lead, we synthesized both atropisomers as phosphodiesterase-4 inhibitors 10. The atropisomers showed significantly different metabolic stabilities while their PDE4 inhibitory activities were somewhat similar. This finding demonstrates the potential utility of stable C-N bond atropisomers in the development of chiral drugs.

Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

An Approach Toward Identification of Target Proteins of Maitotoxin Based on Organic Synthesis

Maitotoxin (MTX) is the principal toxin of ciguatera, a common form of seafood poisoning caused by consumption of fish from subtropical and tropical regions that carry the epiphytic dinoflagellate Gambierdiscus toxicus. Ciguatera is characterized by gastrointestinal, cardiovascular, and neurological disorders, and affects more than 50,000 people annually. MTX is produced by G. toxicusliving on macroalgae, and the toxin accumulates in fish as a result of transfer through the food chain [1]. Although limited supplies of MTX from natural sources have hampered efforts to determine its molecular structure, the Yasumoto and Murata group ultimately elucidated the structure through extensive nuclear magnetic resonance (NMR) analysis [2, 3], and the complete stereochemistry of MTX was determined by the Kishi and Tachibana groups (Fig. 1) [4–7].