HETEROCYCLES

■ Contents

■ Diazirine-Based Multifunctional Photo-Probes for Affinity-Based Elucidation of Protein-Ligand Interaction

Takenori Tomohiro* and Yasumaru Hatanaka

*Graduate School of Medicines and Pharmaceutical Sciences for Research, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

Abstract

Diazirine-based photoaffinity labeling is recognized as one of the most reliable methods for analyzing protein-ligand interactions. Despite its excellent chemical and physical properties, the labeling process consists of an inefficient series of analytical steps: probe preparation, detection and isolation of the target protein, and identification of the labeled site within the active site. Firstly, this review introduces a versatile method for derivatization of trifluoromethylphenyldiazirine, the most common photocross-linker, then discusses its use in optimizing the probe for the simplification of labeled protein analyses including selective detection and purification, and the resulting acceleration of target protein identification by structural analysis. The present review reflects recent achievements in the chemistry and biological application of diazirine photoaffinity probes.

■ Synthesis of 2-Aryl-(Z)-4-(halomethylidene)-4H-3,1-benzoxazines by Sodium Hydride Mediated Cyclization of N-[2-(2,2-Dihaloethenyl)phenyl]arenecarboxamides

Kazuhiro Kobayashi,* Ippei Nozawa, and Daiki Kado

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A simple two-step procedure for the preparation of 2-aryl-(Z)-4-(halomethylidene)-4H-3,1-benzoxazines from readily available 2-(2,2- dihaloethenyl)benzenamines is developed. Thus, these amines were N-aroylated with the respective aroyl chloride to give N-[2-(2,2- dihaloethenyl)phenyl]arenecarboxamides, which in turn were treated with sodium hydride to afford the desired products.

■ A Practical and Scalable Process for the Preparation of 4-Aminophenylboronic Acid Pinacol Ester

Feng Xue,* Chang-Gong Li, Yong Zhu, Tian-Jun Lou, and Guang-Jie He*

*Key Laboratory of Functional Organic Molecules of Xinxiang City Henan Province, College of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang Henan, 453002, China

Abstract

A practical process has been developed for scalable preparation of 4-aminophenylboronic acid pinacol ester through facile two-step procedure. After boron trifluoride etherate efficiently activated the reaction of 4-bromoaniline with diphenyl ketone, metalation reaction of protected 4-bromoaniline with lithium trialkylmagnesiate readily proceeded under mild conditions (−20 °C), which was subsequently subjected to esterification and deprotection reaction to give the 4-aminophenylboronic acid pinacol ester. The improved synthetic route has been successfully scaled up to kilogram quantities in good yield and high quality.

■ Reaction of 5-Methylenehydantoins and Their Chemical Modification to Twin-Drug Type Symmeteical Molecules

Fumiko Fujisaki, Ryou Fujiwara, Miriko Okabe, Ayumi Naito, Enko Fukami, Hatsumi Aki, Nobuhiro Kashige, Fumio Miake, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

We report chemical modifications of 5-methylenehydantoins (3a-e) with various amine nucleophiles to 5-substituted hydantoins and transformations of the obtained hydantoins to new symmetrical twin-drug type bivalent molecules 12 and 13. We also report 5-methylenehydantoin derivatives (3a) with some symmetrical diamines such as piperadine, ethylene-1,2-diamine, and 1,2-phenylenediamine. From trials using diamines such as ethylene-1,2-diamine and 1,2-phenylenediamine, hydantoin ring-opened products 10 and 11 were isolated predominantly.

■ γ-Lactonic and Linear Carboxylic Acids from Cultured Lichen Mycobionts of Graphis scripta

Yukiko Takenaka, Nobuo Hamada, and Takao Tanahashi*

*Organic chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

Spore-derived mycobionts of the lichen Graphis scripta collected in Nikko, Japan, were cultivated on a malt-yeast extract medium supplemented with 10% sucrose to produce three new carboxylic acids 1–3. Their structures were characterized by chemical and spectroscopic methods. These compounds are prototypes of characteristic lichen substances, γ-lactonic and linear carboxylic acids with a long side chain, and were obtained as enantiomeric mixtures.

■ Flavonoids from the Leaves of Nicotiana tabacum and Their Anti-Tobacco Mosaic Virus Activity

Yinke Li, Yingliang Zhao, Nengjun Xiang, Liu Yang, Fei Wang, Guangyu Yang, and Zhengyin Wang*

*College of Resources and Environmental, Southwest University, NO.2 Rd Tiansheng, Beibei District,Chongqing, 400716, China

Abstract

Three new flavonoids, 8-formyl-4'-hydroxy-7-methoxy-6-methyl- flavone (1), 8-formyl-4',7-dimethoxy-6-methylflavone (2), 4',6-dihydroxy- 7-methoxy-8-methoxycarbonylflavone (3) together with two known flavonoids (4 and 5) were isolated from the leaves of Nicotiana tabacum. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-3 were tested for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 1-3 exhibited inhibition rates (%) of 18.4, 22.1 and 16.4, respectively.

■ One-Pot Synthesis of New Benzimidazole Derivatives Promoted by Potassium Carbonate

Meng-Wei Xue, Hong Zhou, Jing-Jing Yang, Jian Li, Shao-Xian Liu, and Dun-Lin Zhang*

*School of Bio-Chemistry and Environmental Engineering, Nanjing Xiaozhuang University, 3601 Hongjing Road, Jiangning District, Nanjing 211171, China

Abstract

An efficient method for synthesis of new benzoimidazoline derivatives has been accomplished via a one-pot reaction of aromatic aldehyde, o-phenylenediamine / 4-Cl-o-phenylenediamine and acetic anhydride promoted by K2CO3. In this method, although aryl substituted aldehydes with electron-releasing substituents did not work in the reaction, a series of aryl substituted aldehydes carrying electron-withdrawing substituents gave the corresponding benzoimidazoline derivatives with good yields of 62 % - 93 %.

■ Facile Synthesis of Benzimidazo[2,1-a]isoindoles from Phenolic Adducts of Ninhydrin

Suven Das* and Arpita Dutta

*Department of Chemistry, Rishi Bankim Chandra College for Women, East Kanthalpara, Naihati, India

Abstract

An efficient synthesis of substituted benzimidazo[2,1-a]isoindoles via the reaction of phenolic adducts of ninhydrin with o-phenylenediamine in EtOH/AcOH under reflux conditions is achieved in single step. The process involves acid-catalyzed rearrangement followed by reaction with o-phenylenediamine.

■ Synthesis and Evaluation of Selenoflavones That Have Potential Neuroprotective Effects

Yong-Sung Choi, Yoon-Jung Kim, Ju Yeun Lee, Jinu Lee, and Jin-Hyun Jeong*

*College of Pharmacy, Yonsei University, 162-1 Songdodong, Yeonsugu, Incheon, Korea

Abstract

We synthesized selenoflavones and evaluated their physicochemical properties and antioxidant effects. When oxygen was substituted with selenium, the compounds exhibited improved polarity and lipophilicity, implying that this change could lead to better BBB penetration. Selenoflavones revealed more potent antioxidant activity in our in-vitro assay. This suggests that selenoflavones would be more druggable than flavones and have a better potential as a neuroprotective agent.

■ A New and Practical Synthesis of Bosutinib

Han Wang, Chunping Zhu, Guoqing Zhu, Xin Tian, Yongjia Shen,* and Yongjun Mao*

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of bosutinib is described on a decagram scale. An intramolecular cyclization of 3-amino-2-(2-bromobenzoyl)- acrylonitrile (22) in K2CO3/DMF condition to form the key 3-cyano-4-hydroxyquinoline intermediate (13) is adopted as the key step. Bosutinib is obtained in 13.7% yield over ten steps and 98.9% purity (HPLC), which make it as a process of cost effective, environmentally friendly and feasible for scale-up operation.