HETEROCYCLES

■ Contents

■ Mesoionic Tetrazoles – Progress Since 1980

Dietrich Moderhack*

*Institute of Medicinal and Pharmaceutical Chemistry, Technical University, Braunschweig, Beethovenstrasse 55, D-38106, Germany

Abstract

This article summarizes the findings made during the past decades with the traditional classes of mesoionic tetrazoles of type (A) and (B); it also deals with the 'abnormal' carbenes derived therefrom. – Emphasis is placed on preparative aspects.

■ Synthesis of Novel Benzimidazoles 2-Functionalized with Pyrrolidinone and γ-Amino Acid with a High Antibacterial Activity

Vestina Strelciunaite,* Kazimieras Anusevicius, Ingrida Tumosiene, Jurate Siugzdaite, Ilona Jonuskiene, Irena Ramanauskaite, and Vytautas Mickevicius

*Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania

Abstract

Series of 2- and 1,2-disubstituted benzimidazoles with carboxyalkyl substituents or their derivatives were synthesized during chemical transformations of 4-(1H-benzimidazol-2-yl)-1-(3-chloro-4-methoxyphenyl)pyrrolidin-2-one. Condensation products of 2-{2-[1-(3-chloro-4-metoxylphenyl)-5-oxo- 3-pyrrolidinyl]-1H-benzimidazol-1-yl}acetohydrazide and 3-(1H-benzimidazol- 2-yl)-4-(3-chloro-4-methoxyphenylamino)butanoic acid hydrazide with mono- and dicarbonylic compounds have been obtained. Some of the synthesized compounds are characterized by a strong bactericidal effect, even at low concentrations.

■ Preparation of Nicotinoyl Amino Acid Derivatives by Fmoc-Solid Phase Synthesis and Preliminary Studies on the DNA-Binding Properties of Nicotinoyl Derivatives

Dongxin Zhao* and Kui Lu*

*School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou 450001, China

Abstract

Three types of nicotinoyl amino acids, i.e., nicotinoyl leucine (NA-Leu), NA-Leu-His, and NA-Tyr-Tyr, were synthesized by Fmoc solid-phase peptide synthesis, purified by reversed-phase HPLC, and characterized by 1H, 13C NMR and ESI-MS. The interactions of nicotinic acid and nicotinoyl derivatives with ctDNA were investigated by fluorescence spectroscopy. NA-Leu-His and NA-Tyr-Tyr exhibited higher affinity for ctDNA compared with free NA, indicating that the imidazolyl of histidine and the phenol group of tyrosine can enhance the embedding interaction of nicotinoyl derivatives into ctDNA. In addition, leucine in the derivatives helped form a special surrounding and spatial structure to interact with ctDNA. The stronger interaction of NA-Tyr-Tyr and NA-Leu-His with ctDNA suggested that the modified nicotinic acid probably erhaps had significant practical value and should be further studied.

■ Synthesis of 6,7-Dihydropyrido[2,3-d]pyrimidin-5(8H)-one Derivatives Based on the Reaction of 1-(4-Chloropyrimidin-5-yl)alk-2-en-1-one Derivatives with Primary Amines

Kazuhiro Kobayashi,* Ryoga Ono, Kouki Ishitobi, Yuuki Chikazawa, Hidetaka Hiyoshi, and Kazuto Umezu

*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 convenient sequence for the synthesis of 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives has been developed. Thus, treatment of 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine with lithium diisopropylamide (LDA) generates 4-chloro-5-lithio-6-methoxy-2- (methylsulfanyl)pyrimidine, which are allowed to react with α,β-unsaturated aldehydes to give the corresponding 1-(4-chloropyrimidin-5-yl)alk-2-en-1-ol derivatives. Oxidation of these alkenols with activated manganese(IV) oxide provides 1-(4-chloropyrimidin-5-yl)alk-2-en-1-one derivatives, of which reaction with a variety of primary amines constitutes tetrahydropyridinone structure to give the desired products.

■ Design, Synthesis, Antitumor and Antimicrobial Activity of Some Novel 6,7-Dimethoxyquinazoline Derivatives

Asmaa E. Kassab,* Ehab M. Gedawy, Zienab Mahmoud, and Rania A. Khattab

*Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kaser El Ainin Street 11562, Egypt

Abstract

Novel 4-substituted-6,7-dimethoxyquinazolines 3, 4a and 4b were synthesized via reacting the corresponding 4-chloro derivative 2 with 2-(4-aminopiperazin-1-yl)ethanol, ethylpiperazine or benzylpiperidine. Quinazolines 6a-c and 8a-d were obtained through reacting 4-hydrazinylquinazoline 5 with different aromatic aldehydes or aromatic isothiocyanates. An attempt to synthesize 6,7-dimethoxyquinazolin-4-yl hydrazinecarboxamides via reacting the hydrazinyl derivative 5 with certain aromatic isocyanates was unsuccessful and the unexpected triazoloquinazoline 7 was obtained regardless to the isocyanate used .The anticancer activity of 4 compounds, namely 3, 4a, 4b and 7 was evaluated by National Cancer Institute (USA) at single dose (10-5 M) utilizing 59 different human tumor cell lines. Moreover, the antimicrobial activity of all the newly synthesized quinazolines was screened against Gram positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram negative bacteria (Escherichia coli and Klebsiella) and a fungal strain (Candida albicans).

■ Experimental Investigation of Tetracyclic Compounds Containing a Nine-Membered Sultam via Cobalt Alkyne Complexes

Kyosuke Kaneda,* Misuzu Fujita, and Risa Naruse

*Hokkaido Pharmaceutical University, 7-Jo 15-4-1 Maeda,Teine,Sapporo,Hokkaido 006-8590, Japan

Abstract

The synthesis, reactivity, and stereochemistry of nine-membered sultams fused with cobalt alkyne complexes using sequential Nicholas and Pauson–Khand reactions are reported. Novel tetracyclic compounds containing nine-membered sultam moieties were characterized by NMR spectroscopy and X-ray crystallography.

■ Design, Synthesis and Evaluation of an L-Dopa-Derived Macrocyclic Hexaoxazole (6otd) as a G-Quadruplex-Selective Ligand

Takahiro Nakamura, Yue Ma, Keisuke Iida, Terumi Ohtake, Hiroyuki Seimiya, and Kazuo Nagasawa*

*Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Abstract

G-Quadruplex (G4) structures in guanine-rich oligonucleotides are involved in replication, transcription and translation processes in cells, and G4 dysfunction is associated with various diseases. Since G4 stabilization is believed to induce growth inhibition, senescence or apoptosis of cancer cells, various G4-stabilizing agents (G4 ligands) have been synthesized, including our recently developed series of macrocyclic polyoxazoles (OTDs). Among OTD derivatives, those bearing side-chain functional groups that interact with phosphate of the DNA backbone show potent G4-stabilizing ability. Here, we report synthesis of a new macrocyclic hexaoxazole bearing two catechol side chains, i.e., D2H4–6M(4)OTD, based upon our previously reported procedure. D2H4–6M(4)OTD showed moderate and selective stabilizing ability towards G4-forming oligonucleotides without altering their topology. It also showed moderate growth-inhibitory activity towards several cancer cell lines.

■ Design, Synthesis and Anticancer Activity of Novel 2,3- and 2,4-Disubstituted Quinazoline and Quinazolinone Derivatives

Maher El-Hashash, Jehan Morsy, Mohamed Azab,* and Naglaa Mahmoud

*Chemistry of Department, Ain Shams University, Abbassia, Cairo 11566, Egypt

Abstract

An acetylhydrazide derivative containing a quinazoline nucleus has been utilized to design and synthesize a series of 2,4-disubstituted quinazolines via reaction with several carbon electrophiles including 4-methoxybenzaldehyde and carbon disulfide as well as acetyl and benzoyl chloride. Another series of 2,3-disubstituted-4(3H)-quinazolinones has been also obtained from reactions of a 3-aminoquinazolin-4(3H)-one derivative with other carbon electrophiles, such as chloroacetamide, acetic anhydride, phenyl isocyanate, and ethyl chloroacetate. The structures of the new compounds have been assigned from their spectral data (IR, 1H NMR, 13C NMR and MS) and elemental analyses. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against breast cancer, hepatocellular carcinoma, cervical cancer, and human promyelocytic leukemia cell lines. All the tested compounds showed anticancer activity.

■ Two New Isoindolin-1-ones from the Leaves of Nicotiana tabacum and Their Anti-Tobacco Mosaic Virus Activities

Guang-Hui Kong, Yu-Ping Wu, Wei Li, Zhen-Yuan Xia, Qiang Liu, Kun-Miao Wang, Pei He, Rui-Zhi Zhu, Xiao-Xi Si, and Guang-Yu Yang*

*Key Laboratory of Tobacco Chemistry of Yunnan Province, China Tobacco Yunnan Industry Company, Hongjin Road 181#, Kunming, 650231, China

Abstract

Two new isoindolin-1-ones, 2-(2-hydroxyethyl)-5-methyl-6-(3- methylbut-2-enyl)isoindolin-1-one (1) and 2,5-dimethyl-6-(3-methylbut-2-enyl) isoindolin-1-one (2), 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 and 2 were tested for their anti-tobacco mosaic virus (anti-TMV) activities. The results revealed that compounds 1 and 2 showed potential anti-TMV activities with inhibition rates of 48.2 and 45.6%, respectively.

■ An Efficient Conversion of Lysine to 2-Aminocaprolactam

Hiroshi Matsumoto, Kouji Kaiso, and Akio Kamimura*

*Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, , Japan

Abstract

Treatment of lysine in wet MeOH at high-temperatures provided a smooth and efficient conversion to 2-aminocaprolactam that is recognized as a potential intermediate for the preparation of bioactive compounds. The obtained 2-aminocaprolactam underwent very rapid racemization under these conditions. A kinetic study of the reaction was performed.

■ Cytotoxic Compounds from Scolopendra subspinipes mutilans

Yu-Ming Liu,* Jian-Bing Nie, Lin-Na Sun, and Qing-Hua Liu

*Department of Pharmacy Engineering, Tianjin University of Technology, No.391, Bin Shui Xi Road, Xi Qing District, Tianjin , China

Abstract

A new amino acid, 2S-3-(1-methyl-1H-imidazol-5-yl)-2-　(methylamino)propanoic acid (1) and a new natural product, 3, 5-dihydroxyquinoline (2), along with a known compound (3) were isolated from the centipede Scolopendra subspinipes mutilans L. Koch. Their structures were elucidated on the basis of extensive one-dimensional (1D)- and 2D-NMR spectroscopic analyses and mass spectrometry. All isolates were evaluated for their cytotoxic activities against three human cancer cell lines, HepG-2, HT-29, and A549. Compounds 2 and 3 exhibited moderate cytotoxic activities with IC50 values of 1.95–27.20 μM against the three cancer cell lines.

■ Inhibition of NF-κB and Cellular Invasion by Novel Flavonoid Dismal in Ovarian Carcinoma Cells

Liyan Wang, Yinzhi Lin, Kulrawee Sidthipong, Jianqiang Tang, Mengjie Li, Takashi Koyano, Thaworn Kowithayakorn, Kengo Sumiyoshi, Tamami Ukaji, and Kazuo Umezawa*

*Molecular Target Medicine, School of Medicine, Aichi Medical university, 1-1 Yazako-Karimata, Nagakute-shi, Aichi 480-1195, Japan

Abstract

In the course of our screening of NF-κB inhibitors, we isolated known flavonoids that inhibit LPS-induced NO production in mouse monocytic leukemia RAW264.7 cells. Since those flavonoids inhibited the NF-κB activity, we have evaluated the inhibitory activity of plant-derived novel flavonoid, desmal, on NF-κB, and found that it inhibits LPS-induced NO production and NF-κB. It also inhibited cellular invasion possibly by the decrease of NF-κB-dependent urokinase-type plasminogen activator. Thus, desmal was found to be a new NF-κB inhibitor having cellular anti-inflammatory and anti-metastatic activities.