Takayasu Yamauchi

Stereocontrolled preparation of cis- and rans-2,6-dialkylpiperidines via diastereoselective reaction of 1-aza-4-oxabicyclo[4.3.0]nonane derivatives with Grignard reagents

Abstract We report here the syntheses of cis - and trans -2,6-disubstituted piperidines using chiral 1-aza-4-oxabicyclo[4.3.0]nonane synthon 1 , which shows high reactivity toward nucleophilic attack at its C-5 position. Bicyclic compounds resembling synthon 1 were transformed to cis - and trans -2,6-disubstituted piperidine derivatives via reactions with various Grignard reagents in a stereospecific manner. Using this methodology, (+)-solenopsin A ( 2b ) and both enantiomers of isosolenopsin A ( 3a and 3b ) were synthesized in an enantioselective manner from a single enantiomeric source.

p‐Dodecylaminophenol derived from the synthetic retinoid, fenretinide: Antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action

Fenretinide, N‐(4‐hydroxyphenyl)retinamide (4‐HPR) is an aminophenol‐containing synthetic retinoid derivative of all‐trans‐retinoic acid, which is a potent chemopreventive and antiproliferative agent against various cancers. Clinical studies of 4‐HPR have shown side effects consisting of night blindness and ocular toxicity. To maintain potent anticancer activity without side effects, p‐dodecylaminophenol (p‐DDAP) was designed based on structure–activity relationships of 4‐HPR. In our study, we investigate whether p‐DDAP shows anticancer activity against human prostate cancer cell line PC‐3 when compared with 4‐HPR. p‐DDAP inhibited PC‐3 cell growth progressively from low to high concentration in a dose‐dependent manner. p‐DDAP was the most potent antiproliferative agent in vitro among 6 p‐alkylaminophenols and 3 4‐hydroxyphenyl analogs examined including 4‐HPR. Cells treated with p‐DDAP were shown to undergo apoptosis, based on condensation nuclei, cytofluorimetric analysis, propidium iodide staining and the expression of bcl‐2 and caspase 3. p‐DDAP arrested the S phase of the cell cycle, while 4‐HPR arrested the G0/G1 phase. In addition, both the i.v. and i.p. administration of p‐DDAP suppressed tumor growth in PC‐3‐implanted mice in vivo. p‐DDAP showed no effects on blood retinol concentrations, in contrast to reductions after 4‐HPR administration. These results indicate that p‐DDAP exhibits excellent anticancer efficacy against hormonal independent prostate cancer in vitro and in vivo, and it may have great potential for clinical use in the treatment of prostate cancer with reduced side effects.

A combination of liposomal sunitinib plus liposomal irinotecan and liposome co-loaded with two drugs enhanced antitumor activity in PC12-bearing mouse

Pheochromocytomas are highly angiogenic neuroendocrine tumors. The side effects of treatment with cytotoxic agents frequently outweigh the benefits. Neuroendocrine tumors are highly angiogenic, dependent on vascular endothelial growth factor and receptor (VEGFR) activation. Sunitinib has antitumor and antiangiogenic activities that target VEGFRs. We investigated the antitumor activity of liposomal sunitinib and irinotecan alone and in combination. Liposomal sunitinib and irinotecan, and liposomes co-loaded with both drugs were prepared, and antitumor activity and biodistribution were examined in nude mice bearing PC12 tumors. Liposomal sunitinib increased in life span (ILS, 14.3%) compared with free sunitinib (−17.1% ILS) with moderate tumor growth suppression, whereas liposomal irinotecan suppressed tumor growth significantly without a survival benefit compared with free irinotecan (−21.7 and −13.3% ILSs, respectively). The combination of liposomal sunitinib plus liposomal irinotecan, and liposomes co-loaded with both drugs, induced significant inhibition of tumor growth and increased life-span more than the combination of free drugs. Accumulation of irinotecan in tumors by the combination of the two liposomal drugs and liposomes co-loaded with both drugs was significantly increased compared with the combination of free drugs. This study provides novel formulations of sunitinib and irinotecan in combination for the treatment of pheochromocytoma.

Asymmetric synthesis of (1R,1′R)- and (1S,1′S)-bis(1-arylethyl)amines by way of a diastereoselective addition to chiral imines and oxaxolidines with organometallic reagents

The asymmetric synthesis of the bis(α-methylbenzyl)amines, (1R,1′R)- and (1S,1′S)-bis(1-arylethyl)-amines 6, utilizing a diastereoselective reaction of chiral imines and oxazolidines derived from (R)-phenylglycinol with Organometallic reagents, is described.

Concise total synthesis of (-)-deoxocuscohygrine and (-)-dihydrocuscohygrine.

The concise enantioselective total synthesis of C(2)-asymmetrical (-)-deoxocuscohygrine and (-)-dihydrocuscohygrine are described. Double-diastereoselective additions of normal Grignard reagent to bis(1,3-oxazolidine) have been deployed to construct chiral diamine fragments as a key step.

Facile Asymmetric Synthesis of Aziridine Derivatives via the Diastereoselective Reaction of Chiral Imines with Dimethylsulfonium Methylide

A simple method for the synthesis of chiral 2-substituted aziridine derivatives is described. The reaction pathway consists of the diastereoselective addition of dimethylsulfonium methylide to chiral imines derived from (R)-phenylglycinol and various aldehydes.

Effect of p-aminophenols on tyrosinase activity.

Tyrosinase is involved in the synthesis of melanin in the skin and hair as well as neuromelanin in the brain. This rate limiting enzyme catalyzes two critical steps (reactions) in melanogenesis; the hydroxylation of tyrosine to form DOPA and the subsequent oxidation of DOPA into dopaquinone. Several new aminophenol derivatives have been synthesized based on structure-activity relationship studies of N-(4-hydroxyphenyl)retinamide (1), a derivative of retinoic acid. In order to find new tyrosinase inhibitors, we investigated the effects of these p-aminophenols, including p-decylaminophenol (3), on the activity of mushroom tyrosinase. Compound 3 was the most potent agent, showing significant inhibition as compared with control. The inhibitory effects of 3 on tyrosinase activities were greater than seen with kojic acid, a well-known potent inhibitor of tyrosinase activity, which also causes adverse effects, including rash and dermatitis. A Lineweaver-Burk kinetic analysis of inhibition showed that 3 suppresses tyrosinase activity in a non-competitive fashion for both substrates, tyrosine and DOPA. These results suggest that 3 might be a useful alternative to kojic acid as a tyrosinase inhibitor.

Synthesis of C2-symmetrical chiral diamines: diastereoselective addition to bis(1,3-oxazolidinyl)alkanes with Grignard reagents

Abstract Asymmetric syntheses of C 2 -symmetrical chiral 1,4- and 1,5-diamines with stereogenic centers adjacent to the nitrogen atom have been accomplished. Chiral diamines were prepared by diastereoselective alkylations of bisoxazolidine, which was derived from ( R )-phenylglycinol. Methyl and phenyl Grignard reagents were employed as alkylating reagents. In addition, tertiary chiral diamines were readily converted to primary diamines in high yield.

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure-Activity Relationship Study of Matrine Alkaloids.

The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3- and 4-substituents influenced the effect mediated through the KOR.

REGIO-AND STEREOSELECTIVE RING-OPENING REACTION OF CHIRAL AZIRIDINES : A FACILE SYNTHESIS OF CHIRAL β-AMINO ALCOHOLS

The reaction of chiral 2-alkylsubstituted aziridines (1a-d) with acetic acid afforded β-amino alcohols with an (S)-chiral center at the β position (with respect to oxygen). In contrast, a reaction of the same chiral aziridines with acetyl chloride followed by treatment with water gave β-amino alcohols that have an (S)-chiral center at the a position. In addition, the reaction of the same chiral aziridines with benzyl bromide followed by treatment with 2% sulfuric acid gave the β-amino alcohols with an (R)-chiral center at the a position. Thus, we could control the regioselectivity and stereoselectivity of the ring-opening reaction of chiral aziridines (1a-d).