Reiko Ikeda

Highly selective conversion of nitrobenzenes using a simple reducing system combined with a trivalent indium salt and a hydrosilane

Controlling the type of indium salt and hydrosilane enables a highly selective reduction of aromatic nitro compounds into three coupling compounds, azoxybenzenes, azobenzenes and diphenylhydrazines, and one reductive compound, anilines.

A Single-Step Synthesis of Enynes: Pd-Catalyzed Arylalkynylation of Aryl Iodides, Internal Alkynes, and Alkynylsilanes

An unprecedented single-step synthesis of enyne derivatives through Pd-catalyzed arylalkynylation of aryl iodides, internal alkynes, and alkynylsilanes is described.

Copper-Catalyzed [5 + 1] Annulation of 2-Ethynylanilines with an N,O-Acetal Leading to Construction of Quinoline Derivatives

A novel copper-catalyzed [5 + 1] annulation of 2-ethynylanilines with an N,O-acetal, which functioned as a C1 part, leading to the preparation of quinoline derivatives with an ester substituent on the 2-position is described. A combination of CuBr(2) and trifluoroacetic acid (TFA) promoting [5 + 1] annulation of the 2-ethynylaniline with ethyl glyoxylate is also demonstrated.

3-benzylamino-β-carboline derivatives induce apoptosis through G2/M arrest in human carcinoma cells HeLa S-3.

β-carboline derivatives are known as the lead compounds for anti-tumor agents. To examine an optimal structure for anti-tumor activity, we synthesized a variety of β-carboline derivatives, possessing a variety of substituents on the nitrogen atom of the amino group of 3-amino-β-carboline, and evaluated their anti-tumor activity for HeLa S-3 cell line. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that an optimal structure for anti-tumor activity was 3-cyclohexylmethylamino (1e) or 3-benzylamino-β-carboline (1f). An optimal counter anion of 2-methyl-3-benzylamino- β-carbolinium salts was a triflate anion 2c. In addition, the introduction of a hydroxyl group on the meta-position of the benzyl group of 3-benzylamino-β-carboline (3e) enhanced its anti-tumor activity. Hoechst 33342 staining and DNA fragmentation assay suggested that 1f, 2c and 3e induced cell death by apoptosis unlike 1e. Flow cytometry analysis showed that 1f, 2c and 3e induced cell apoptosis through arrest of the cell cycle in the G2/M phase.

Single-step thioetherification by indium-catalyzed reductive coupling of carboxylic acids with thiols.

Direct thioetherification from a variety of aromatic carboxylic acids and thiols using a reducing system combined with InBr(3) and 1,1,3,3-teramethyldisiloxane (TMDS) in a one-pot procedure is demonstrated. It was also found that a system combined with InI(3) and TMDS underwent thioetherification of aliphatic carboxylic acids with thiols.

Structure–activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-β-carboline derivatives

We synthesized 47 kinds of 3-amino- or 3-benzylamino-β-carboline derivatives with a substituent on the 6-, 8-, or 6,8-carbon atoms and evaluated their antitumor activities for Hela S-3 and Sarcoma 180 cell lines using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Consequently, we succeeded to develop 3-benzylamino-8-methylamino-β-carboline (17a) and 8-methylamino-3-(3-phenoxybenzyl)amino-β-carboline (17c) with antitumor activity with IC(50) values of 0.046, 0.032 μM, respectively, against HeLa S-3 cell line, which are higher than that of previously reported 3-(3-phenoxybenzyl)amino-β-carboline (10e) of 0.074 μM. Furthermore, effects of Cl group at 6-carbon atom on the type of cell death was evaluated using 3-benzylamino-6-chloro-β-carboline (10b), 3-benzylamino-β-carboline (10d), N-(3-benzylamino)-6-chloro-9H-β-carbolin-8-yl)benzamide (14g), and N-(3-benzylamino-9H-β-carbolin-8-yl)benzamide (17b) to show no effect. Hoechst 33342 staining and DNA fragmentation assay suggested that these compounds induced cell death by apoptosis. In addition, using flow cytometry analysis, we established that the cell death pathway was through the arrest of the cell cycle in the G(2)/M phase.

3-(3-Phenoxybenzyl)amino-β-carboline: A novel antitumor drug targeting α-tubulin

3-(3-Phenoxybenzyl)amino-β-carboline 2h showed extremely-high activity; the IC(50) value was 0.074 μM. To verify 2h-induced cell death types, we observed the chromatin condensation, the DNA fragmentation and activated caspase-3 using Hoechst 33342, agarose electrophoresis and western blot, and suggesting 2h-induced cell death type was apoptosis. Flow cytometry showed that 2h-treated cell was induced SubG1 cell population after G2/M cell cycle arrest. In addition, using affinity chromatography and peptide mass fingerprinting, we found that interacting protein with this compound was α-tubulin protein.

Synthesis of Tri‐ or Tetrasubstituted Pyrimidine Derivatives through the [5+1] Annulation of Enamidines with either N,N‐Dimethylformamide Dialkyl Acetals or Orthoesters and Their Application in a Ring Transformation of Pyrimidines to Pyrido[2,3‐d]pyrimidin‐5‐one Derivatives

The [5+1] annulation of enamidines, which were prepared from functionalized silanes, organolithium compounds and two nitriles, with N,N-dimethylformamide dialkyl acetals as the C1 unit is described, leading to the synthesis of tri- and tetrasubstituted pyrimidine derivatives under catalyst- and solvent-free reaction conditions. Furthermore, the [5+1] annulation of enamidines by using orthoesters as the C1 unit is described, in which catalytic amounts of ZnBr(2) catalyze the annulation to produce polysubstituted pyrimidines under toluene or xylene reflux conditions. Moreover, the combination of a reductive ring-opening reaction with [Mo(CO)(6)] and a subsequent intramolecular cyclization with tBuOK effectively causes a skeletal transformation from the pyrimidines containing an isoxazolyl and an ethoxy substituent to form pyrido[2,3-d]pyrimidin-5-one frameworks in excellent yield.

Hf(OTf)4-catalyzed regioselective n-aminomethylation of indoles and related NH-containing heterocycles.

Under Lewis acidic conditions using Hf(OTf)(4), the aminomethylation of an indole derivative with a typical N,O-acetal preferentially produced kinetically favored N-aminomethylated indole derivatives instead of thermodynamically favored 3-aminomethylated indoles.

Indium(III)-Catalyzed Reductive Bromination and Iodination of Carboxylic Acids to Alkyl Bromides and Iodides: Scope, Mechanism, and One-Pot Transformation to Alkyl Halides and Amine Derivatives

Highly effective indium(III)-catalyzed reductive bromination or iodination of a variety of carboxylic acids with 1,1,3,3-tetramethyldisiloxane (TMDS) and a source of bromine or iodine is described. This functional group interconversion has high tolerance for several functional groups, such as halogens, a hydroxy group, a nitro group, an olefin part, and a sulfide moiety. This indium catalytic system is also applicable to the reductive iodination of aldehyded, acyl chlorides, and esters. Furthermore, this reducing system can be applied to the one-pot synthesis of alkyl halides and amine derivatives via the addition of nucleophiles. Insight into the reaction mechanism was gained via the time course of (1)H and (13)C NMR monitoring experiments and the corresponding stepwise reactions.