HETEROCYCLES

■ Contents

■ Bridged Nucleosides as Building Blocks of Oligonucleotides: Synthesis and Properties

Yoshiyuki Hari*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan

Abstract

Bridging between the 2ʹ- and 4ʹ-carbons in a nucleoside restricts the furanose ring to C3ʹ-endo conformation, which coincides with the sugar conformation in an oligonucleotide forming a duplex with single-stranded RNA (ssRNA) and a triplex with double-stranded DNA (dsDNA). Therefore, oligonucleotides modified by 2ʹ,4ʹ-bridged nucleosides generally increase hybridization ability with ssRNA and dsDNA when compared with the natural oligonucleotide. Till date, a large number of 2ʹ,4ʹ-bridged nucleosides with additional two-atom to four-atom bridges between 2ʹ- and 4ʹ-carbons have been developed by many research groups including our group. For this, ionic cyclization, ring-closing metathesis, and radical cyclization have been used so far as the synthetic strategies of bridge constructions. Based on such a background, we recently proposed a 2ʹ,4ʹ-bridged nucleoside possessing 6ʹ-oxygen founded on a new design concept and several types of analogs including 2ʹ-O,4ʹ-C-ethyleneoxy-bridged 5-methyluridine with a four-atom bridge have been developed. In addition, as a new strategy of bridge construction, radical cyclization using the 4ʹ-carbon radical of a nucleoside was exemplified and a promising 2ʹ,4ʹ-bridged nucleoside, the 6ʹ-methyl analog of 2ʹ-O,4ʹ-C-ethylene-bridged 5-methyluridine, was found. This review mainly focuses on our recent results on bridged nucleosides used for chemically modified oligonucleotides. It describes the design and synthesis of the bridged nucleosides, along with the properties of oligonucleotides including bridged nucleosides.

■ Transition Metal-Free Cyclization of N-Boc-N-propargylenamines

Yuya Chikayuki, Yasuaki Kouno, Shiori Yonekawa, Haruka Ishikawa, Yoko Waki, Hiroyoshi Teramoto, Shigeru Sasaki, Kimio Higashiyama, and Takayasu Yamauchi*

*Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

An efficient method for the synthesis of multi-substituted pyrroles was developed using basic cyclization of readily accessible N-Boc-N-propargylenamines. Despite the basic conditions, cleavage of the N-Boc group occurred easily. The process was rapid and afforded N-H-pyrroles with wide functional group tolerance in high yields.

■ Copper-catalyzed β-Iodovinylation of Azole and Pyrrole Derivatives

Simon Ricard, François Ladouceur, Guillaume Couture, and Benoit Daoust*

*Department of Chemistry, Biochemistry and Physics, University of Quebec in Trois-Rivieres, CP. 500, Trois-Rivieres, Quebec, Canada

Abstract

Herein is described an efficient copper-catalyzed synthesis of β-iodovinyl-azole and β-iodovinyl-pyrrole derivatives using (E)-1,2-diiodoethene which was efficiently applied to azole and pyrrole derivatives in both organic and hydro-organic medium to afford the corresponding β-iodovinylated adducts in up to excellent yields with complete stereocontrol. These nitrogenated vinyl iodides can be further functionalized into disubstituted olefins through various metal catalyzed coupling reactions.

■ Regioselective Synthesis of Quinoxalin-2-one Derivatives Regulated by Acid and Base

Wanli Liu, Qifeng Su, Kang Qiu, Meng Wang,* and Qun Lu*

*School of Life Science and Engineering, Southwest Jiaotong University, NO.111, North Second Ring Road Chengdu 610031, Sichuan, China

Abstract

A concise approach for the synthesis of quinoxalin-2-one derivatives through substituted o-phenylenediamines and α-ketoester with high regioselectivity is developed. Interestingly, the two regioisomers can be selectively obtained and the regioselectivity can be regulated by acid and base. The typical regioisomer ratio is up to 15:1 in acidic conditions and it can be easily reversed as 1:4 in basic conditions.

■ Design, Synthesis and in vitro Antifungal Evaluation of Novel Triazole Derivatives

Guoqing Sui,* Li Ren, Ruiyuan Liu, Dan Xu, Hongdong Hao,* and Wenming Zhou*

*College of Chemistry & Pharmacy, Northwest A ＆ F University, No. 22 Xinong Road, Yangling, Shaanxi Province 712100, China

Abstract

As a part of our continuing research on triazole derivatives antifungal agents, 10 novel target compounds containing 1,2,4-triazole moiety were synthesized and characterized by the spectroscopic analysis, and their in vitro antifungal activities against four phytopathogenic fungi were assayed systematically. Especially, compound 3c displayed excellent activity against F. graminearum with the median effective concentration value (EC50) of 5.03 µg/mL, and the value was extremely close to that of tebuconazole (EC50 = 3.13 μg/mL). Generally, for carbonyl compounds containing morpholine moiety, introducing 4-F to benzene ring obviously improved activities against most of tested fungi in varying degree.

■ Synthesis and Cytotoxic Evaluation of Steroidal Endoperoxide Derivatives with Hydrazide Side Chain as Anticancer Agents

Yinglong Han, Yu Lin, Yongmei Wang, Haijun Wang, Hongling Li, Jing Wang, Yukun Ma, and Ming Bu*

*College of Pharmacy, Qiqihar Medical University, No 333, Bukui North Street, Jianhua District, Qiqihar, China

Abstract

A series of novel steroidal 5α,8α-endoperoxide derivatives bearing hydrazide side chain were synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, HCT-116, MCF-7, and A549) using the MTT assay in vitro. The results showed that compound 6k exhibited significant cytotoxic activity against HepG2 cells (IC50 = 5.60 μM). Further cellular mechanism studies in HepG2 cells indicated that compound 6k triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential (MMP) which was associated with up-regulation of Bax, down-regulation of Bcl-2.

■ Synthesis of Methylophiopogonanone A

Ryo Katagiri, Yoshinori Uekusa, Yuji Narukawa, and Fumiyuki Kiuchi*

*Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

Ophiopogon Root (root of Ophiopogon japonicus Ker-Gawler, Liliaceae) is a crude drug used as expectorant, anti-cough and tonic in Kampo medicine (traditional Japanese medicine) as well as other traditional medicines of Asian countries. It contains characteristic homoisoflavonoids with methylated ring A. We synthesized methylophiopogonanone A (1), which is a candidate marker compound for identification test of Ophiopogon Root, from phloroglucinol in 9 steps with overall yield of 11.1%

■ Efficient Synthesis of Some New 1,3,4-Thiadiazole and Thiazole Derivatives via Thiosemicarbazone Derivatives

Mohamed Abdelmonem Raslan*

*Department of Chemistry, Faculty of Science, Aswan University, Aswan 81528, Egypt

Abstract

We reported here reactions of hydrazinecarbodithioate and hydrazinecarbothioamide derivatives with hydrazonoyl chloride derivatives to afford 1,3,4-thiadiazole and thiazole derivatives, respectively. Also, reactions of hydrazinecarbothioamide derivatives with α-halo esters derivatives, diethyl acetylenedicarboxylate and chloroacetonitrile afforded thiazole derivatives. The structures of the newly synthesized compounds were established based on its elemental analyses and spectral data.