Kenya Nakata

Kinetic Resolution of Racemic α-Arylalkanoic Acids with Achiral Alcohols via the Asymmetric Esterification Using Carboxylic Anhydrides and Acyl-Transfer Catalysts

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic alpha-substituted carboxylic acids using achiral alcohols, aromatic or aliphatic carboxylic anhydrides, and chiral acyl-transfer catalysts. The combination of 4-methoxybenzoic anhydride (PMBA) or pivalic anhydride with the modified benzotetramisole-type catalyst ((S)-beta-Np-BTM) is the most effective for promotion of the enantioselective coupling reaction between racemic carboxylic acids and a novel nucleophile, bis(alpha-naphthyl)methanol, to give the corresponding esters with high ees. This protocol was successfully applied to the production of nonracemic nonsteroidal anti-inflammatory drugs from racemic compounds utilizing the transacylation process to generate the mixed anhydrides from the acid components with the suitable carboxylic anhydrides.

Kinetic Resolution of the Racemic 2-Hydroxyalkanoates Using the Enantioselective Mixed-Anhydride Method with Pivalic Anhydride and a Chiral Acyl-Transfer Catalyst

A variety of optically active 2-hydroxyalkanoates and the corresponding 2-acyloxyalkanoates are produced by the kinetic resolution of racemic 2-hydroxyalkanoates by using achiral 2,2-diarylacetic acid with hindered carboxylic anhydrides as the coupling reagents. The combined use of diphenylacetic acid, pivalic anhydride, and (+)-(R)-benzotetramisole ((R)-BTM) effectively produces (S)-2-hydroxyalkanoates and (R)-2-acyloxyalkanoates from the racemic 2-hydroxyalkanoates (s-values=47-202). This protocol directly provides the desired chiral 2-hydroxyalkanoate derivatives from achiral diarylacetic acid and racemic secondary alcohols that do not include the sec-phenethyl alcohol moiety by using the transacylation process to generate the mixed anhydrides from the acid components with bulky carboxylic anhydrides under the influence of the chiral acyl-transfer catalyst. The transition state that provides the desired (R)-2-acyloxyalkanoate from (R)-2-hydroxyalkanoate included in the racemic mixture is disclosed by DFT calculations, and the structural features of the transition form are also discussed.

2,2-DISUBSTITUTED PROPIONIC ANHYDRIDES : EFFECTIVE COUPLING REAGENTS FOR THE KINETIC RESOLUTION OF SECONDARY BENZYLIC ALCOHOLS USING BTM

A variety of optically active benzylic alcohols possessing aliphatic substituents at the C-1 position are produced by the kinetic resolution of racemic secondary alcohols using free carboxylic acids with 2,2-disubstituted propionic anhydrides and (+)-benzotetramisole (BTM). Evaluation of the efficiency of this asymmetric esterification using several anhydrides derived from aliphatic carboxylic acids were carried out by comparing the efficiencies of the kinetic resolution of (±)-l-phenyl-1-propanol. It was found that not only pivalic anhydride is a very widely usable reagent to produce the corresponding esters with high ees in the presence of BTM, but other 2,2-disubstituted propionic anhydrides, such as 2-methyl-2-phenylpropionic anhydride (MPPRA) and 2,2-diphenylpropionic anhydride (DPPRA), are also applicable as effective coupling reagents for producing the optically active esters and alcohols with high selectivities. This protocol directly provides chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the transacylation process to generate mixed anhydrides from the acid components and sterically hindered carboxylic anhydrides.

Kinetic resolution of racemic 2-hydroxy-γ-butyrolactones by asymmetric esterification using diphenylacetic acid with pivalic anhydride and a chiral acyl-transfer catalyst.

Various optically active 2-hydroxy-γ-butyrolactone derivatives are produced via the kinetic resolution of racemic 2-hydroxy-γ-butyrolactones with diphenylacetic acid using pivalic anhydride and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst. Importantly, the substrate scope of this novel protocol is fairly broad (12 examples, s-value; up to over 1000). In addition, we succeeded in disclosing the reaction mechanism to afford high enantioselectivity using theoretical calculations and expounded on the substituent effects at the C-3 positions in 2-hydroxylactones.

An effective kinetic resolution of racemic secondary benzylic alcohols using 3-pyridinecarboxylic anhydride and a chiral acyl-transfer catalyst in the absence of tertiary amine

3-Pyridinecarboxylic anhydride (3-PCA) was found to function as an efficient coupling reagent for the kinetic resolution of racemic secondary benzylic alcohols with achiral carboxylic acids in the presence of a catalytic amount of (+)-BTM. A variety of optically active carboxylic esters are produced with high enantiomeric excesses by this new chiral induction system without using a tertiary amine.

Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents

Four pseudo-symmetrical tamoxifen derivatives, RID-B (13), RID-C (14), RID-D (15), and bis(dimethylaminophenetole) (16), were synthesized via the novel three-component coupling reaction, and the structure-activity relationships of these pseudo-symmetrical tamoxifen derivatives were examined. It was discovered that 13 and 16 strongly inhibit the viability of the HL-60 human acute promyelocytic leukemia cell line, whereas 14 possesses a medium activity against the same cell line and 15 has no effect on the cell viability. The global anti-tumor activity of 13-16 against a variety of human cancer cells was assessed using a panel of 39 human cancer cell lines (JFCR 39), and it was shown that RID-B (13) strongly inhibited the growth of several cancer cell lines at concentrations of less than 1 microM (at 0.38 microM for SF-539 [central nervous system], at 0.58 microM for HT-29 [colon], at 0.20 microM for DMS114 [lung], at 0.21 microM for LOX-IMVI [melanoma], and at 0.23 microM for MKN74 [stomach]).

4-(Dimethylamino)pyridine N-oxide (DMAPO): an effective nucleophilic catalyst in the peptide coupling reaction with 2-methyl-6-nitrobenzoic anhydride.

Various carboxamides or peptides were synthesized from the corresponding carboxylic acids and amines or alpha-amino acids in high yields by the catalysis of 4-(dimethylamino)pyridine N-oxide (DMAPO) with 2-methyl-6-nitrobenzoic anhydride (MNBA). Because the segment-coupling reaction of alpha-amino acids proceeds through the effective activation of the carboxylic acid moieties with DMAPO in the presence of tertiary amines under mild conditions, undesired racemization was hardly observed in the synthesis of oligopeptides such as Z-Gly-Phe-Val-OMe, Z-Phe-Val-Ala-OMe, and Bz-Val-Val-OMe.

Induction of mitochondria‐involved apoptosis in estrogen receptor‐negative cells by a novel tamoxifen derivative, ridaifen‐B

Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor‐positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor‐negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis‐inducing effect of tamoxifen and evaluated the apoptosis‐inducing pathway. The estrogen receptor‐positive human leukemia cell line HL‐60 and estrogen receptor‐negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability‐detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen‐B had more potent cancer cell‐damaging activity than tamoxifen. Ridaifen‐B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen‐B‐induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen‐B‐induced apoptosis was estimated. Ridaifen‐B significantly reduced mitochondrial membrane potential, and overexpression of Bcl‐2 inhibited ridaifen‐B‐induced apoptosis. These results suggest that the induction of apoptosis by ridaifen‐B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement. (Cancer Sci 2008; 99: 608–614)

A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor

In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound 6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure-activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound 25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors.

Novel tamoxifen derivative Ridaifen-B induces Bcl-2 independent autophagy without estrogen receptor involvement.

Autophagy is a self-proteolysis process in eukaryotic cells that results in the sequestering of intracellular proteins and organelles in autophagosomes. Activation of autophagy progress continued growth of some tumors, instead extensive autophagy induces cell death. In a previous study, we synthesized a novel tamoxifen derivative, Ridaifen (RID)-B. RID-B induced mitochondria-involved apoptosis even in estrogen receptor (ER)-negative cells. Since tamoxifen induces autophagy other than apoptosis, we treated ER-negative Jurkat cells with RID-B in the present study. RID-B treatment induced apoptosis and LC3 and lysosome colocalization, which results in the formation of autolysosomes. Western blotting revealed that LC3 was converted to LC3-I to LC3-II with RID-B treatment, suggesting that RID-B induced autophagy without ER involvement. Moreover, overexpression of the anti-apoptotic protein Bcl-2 suppressed the RID-B-induced cell death, but not the induction of autophagy. These results presumed that RID-B-induced autophagy is independent of Bcl-2, making RID-B-induced autophagy different from RID-B-induced apoptosis. Since Beclin 1 level is unchanged during RID-B treatment, RID-B induced autophagy pathway is Bcl-2/Beclin1 independent noncanonical pathway.