HETEROCYCLES

■ Contents

■ Chemistry of Anti-HIV Active Trimeric Pyranonaphthoquinone Conocurvone: Synthetic Studies towards Monomeric Teretifolione B and Related Compounds

Takuya Kumamoto* and Kazuaki Katakawa

*Department of Synthetic Organic Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan

Abstract

Pyranonaphthoquinone natural products are widely distributed in plants and microorganisms and have diverse biological activities. Angular benzochromenes are a small class of natural products isolated from Conospermum and Pentas plants. Of these, conocurvone was isolated from Conospermum as a trimeric pyranonaphthoquinone that has potent anti-HIV activity. We have focused on the total synthesis of compounds that exhibit biological activity or whose activity is enhanced upon oligomerization. This review describes the discovery and biological activities of the trimeric pyranonaphthoquinone conocurvone and related compounds, as well as our and other researchers’ synthetic studies toward monomeric pyranonaphthoquinones.

■ Natural Products for Biocides Discovery: Discovery of Arundine and It’s Derivatives as Novel Antiviral and Anti-Phytopathogenic-Fungus Agents

Ancai Liao, Shengli Jin, Ziwen Wang,* and Qingmin Wang*

*Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, College of Chemistry, Tianjin Normal University, No.393, Extension of Bin Shui West Road, Xi Qing District, Tianjin 300387, China

Abstract

Plant diseases are one of the natural disasters that seriously harm agricultural production, and it is very difficult to control. The discovery of new antiviral and antifungal lead compounds becomes more and more important. Natural product arundine was found to have anti-tobacco mosaic virus (TMV) activity and anti-phytopathogenic-fungus activity for the first time. A series of arundine analogues were designed, synthesized and evaluated for their antiviral and fungicidal activities. Compound 6 with excellent antiviral activity emerged as novel antiviral lead compound. Compound 7 with 12.6−38.3 μg/mL EC50 values against 14 plant pathogens emerged as novel antifungal lead compound. This work laid a foundation for promoting the application of arundine analogues in plant protection.

■ Preparation and Cytotoxic Evaluation of Vouacapane Oxidation Products

Armando Talavera-Alemán, Mario A. Gómez-Hurtado, Gabriela Rodríguez-García, Alejandra Ochoa-Zarzosa, Christine Thomassigny, Carlos M. Cerda-Garcia-Rojas,* Pedro Joseph-Nathan, and Rosa E. del Río*

*Department of Chemistry, CINVESTAV-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, C.P. 07000, Mexico, D.F., Mexico

Abstract

Treatment of (−)-(5S,6R,8S,9S,10R,14R)-6-acetoxyvouacapane (1) with DDQ, mCPBA, or Cr(VI) reagents afforded diterpenoids with various degrees of oxidation at the furan and C rings. Oxidation of 1 using DDQ provided the known benzofuran 2, together with the new derivatives dimer 3, lactone 4, and aldehyde 5, while mCPBA oxidation gave 2, spirocassenolide 6, and cassenolides 7 and 8a. Oxidation of 1 with CrO3 gave 4, 6, 8a, and spirocassenolide 9, while the use of K2Cr2O7 yielded 4, 9, and spirocassenolide 10. The structures of the new compounds followed from HRMS, NMR measurements, and by single-crystal X-ray diffraction of 3, 4, 8b, and 10. Compounds 1, 2, and 6 were evaluated for their cytotoxic activity against the MCF-7 and HL-60 cancer cells, showing moderate cytotoxic activity.

■ Concise Synthesis and Evaluation of ortho-Naphthoquinones Containing a Phenolic Hydroxy Moiety

Mitsuaki Yamashita, Syuhei Hata, Jun Sawano, Ryuji Umeda, and Akira Iida*

*School of Agriculture, Kindai University, Nakamachi, Nara 631-8505, Japan

Abstract

A concise and efficient synthesis method for the preparation of antiproliferative ortho-naphthoquinones is described. Notably, the synthesis of ortho-furanonaphthoquinone was achieved by utilizing a regioselective oxidative conjugate addition of dimethylamine and the Sonogashira coupling/cyclization reaction as the key steps. Additionally, an improved synthesis of hydroxy-β-lapachone was established and included a regioselective prenylation by directed ortho-lithiation. In vitro antiproliferative effects of the synthesized analogs against a panel of 39 human cancer cell lines were evaluated and the results were directly compared to those previously obtained for 1.

■ A Facile Synthesis of 4-Substituted Glutamate Derivative via 1,3-Dipolar Cycloaddition of Dimethyl 2- Methyleneglutarate and Nitrone Derived (-)-Menthone

Abigail Kempf, Jaffarguriqbal Singh, Dina C. Merrer, and Richard Washington Denton*

*Chemistry And Environmental Science, Medgar Evers College- CUNY, 142- Home Street, Valley Stream, NY 11580

Abstract

The 1,3-dipolar cycloaddition reaction of dimethyl 2-methyleneglutarate and (-)-menthone-derived nitrone occurred with moderate selectively to produce the desired isoxazolidine which was a direct precursor to the (2S,4S)-substituted glutamate derivative in an overall yield of 20%. The possibility of preparing the unnatural amino acid, (S)-(+)-lycoperdic acid was studied based on its evidence within the mass spectra of the final product.

■ Synthesis and Biological Evaluation of NMDI14 Derivatives as Anti-Mesothelioma Agents

Hong Nhung Nguyen, Koya Suzuki, Yasuaki Kimura, Takatsugu Hirokawa, Yuko Murakami-Tonami, and Hiroshi Abe*

*Graduate School of Sceince, Nagoya University, Furo, Chikusa, Nagoya, Aichi 464-8602, Japan

Abstract

Mesothelioma is a severe tumor formed in pleura and peritoneum, for which no useful molecular-targeting therapy is available. We synthesized several derivatives of NMDI14, which is a reported inhibitor for non-sense mediated mRNA decay, and evaluated the activity of the NMDI14 derivatives as potential anti-mesothelioma agents. Some of the synthesized compounds showed promising activity in terms of cytotoxicity toward mesothelioma model cells and promotion of GAS5 expression selectively in mesothelioma cells. These results indicate that the NMDI14 derivatives may be useful for further developing clinically effective anti-mesothelioma drugs.

■ Three New Furan-2-Carboxylic Acid Derivatives from the Stem Bark of Nicotiana tabacum and Their Bioactivity

Yin-Ke Li, Na Lv, Dian Luo, Wei-Song Kong, Qi-Li Mi, Qian Gao, Wan-Li Zeng, Jing Li, Jun Ling, Chun-Bo Liu, Guang-Yu Yang, Xue-Mei Li, Zhang-Yu Chen,* and Qiu-Fen Hu*

*Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650031, China

Abstract

Three new (1-3), together with three known (4-6) furan-2-carboxylic acid derivatives were isolated from the stem bark of Nicotiana tabacum. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1~6 were tested for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1-6 showed good inhibition with IZD of 12.8±2.3, 13.5±1.8, 14.3 ±2.2, 15.1 ±2.0, and 14.7±2.2 mm. Compounds 1-6 were also tested for the antioxidant activity, and they showed notable antioxidant activity with an IC50 value of 3.86, 4.05, 3.62, 4.11, 3.57, and 3.64 μg/mL, respectively.

■ New and Convergent Synthesis of AZD 4547

Lehao Bu, Han Wang,* Wenxin Chen, Lei Gao, Cong Sun, and Yongjun Mao

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

Abstract

A practical and convergent synthetic route of AZD 4547 was developed successfully. The intermediate 5-(3,5-dimethoxyphenylethyl)-1H- pyrazol-3-amine (7) was prepared from 3,5-dimethoxybenzaldehyde through 6 simple steps in 52.3% yield. Another intermediate 4-((3S,5R)-3,5- dimethylpiperazin-1-yl)benzoic acid (14) was synthesized from ethyl 4-fluorobenzoate and (2R,6S)-2,6-dimethylpiperazine in 62% yield over 2 steps. Finally, AZD 4547 was obtained from 7 and 14 in 73% yield and 99.1% purity. Purification methods of the intermediates and the final product involved in the route were developed.

■ Synthesis and Cytotoxic Activity of Some New Bipyrazole Derivatives

Bader A. Salameh,* Kayed A. Abu-Safieh,* Islam S. AL-Aqrabawi, Fatima Alsoubani, and Lubna H. Tahtamouni

*Department of Chemistry, Faculty of Science, Hashemite University, P.O. Box 330127 Zarqa, 13133, Jordan

Abstract

A new series of bipyrazole derivatives were prepared and characterized via the reaction of 5-hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole with various 1,3-dicarbonyl compounds. The synthetic pathway was based on the classical Knorr pyrazole synthesis. In vitro cytotoxic activity of the fully characterized bipyrazole derivatives was determined and their IC50 values were also reported.