HETEROCYCLES

■ Contents

■ Synthesis and Chemistry of Phosphorus Compounds Substituted by 1,2,4-Triazine Moieties as Medicinal Probes

Abdulrahman S. Alharbi* and Reda M. Abdel-Rahman

*Department of Chemistry, Faculty of Science, King Abdul Aziz University, P.O. Box. 42805 Jeddah, 21551, Saudi Arabia

Abstract

Design, synthesis, and chemical behaviors of various phosphorus compounds containing and/ or bearing 1,2,4-triazine moieties are received. Besides, the medicinal, biocidal, and biological activities of these targets were reported. A relation between P-C, P-O, P-N, and P-S bonds was also studied.

■ Chemical Transformation of Chromones into Coumarins

Aya Ahmed, Magdy A. Ibrahim, and Al-Shimaa Badran*

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711, Cairo-Egypt

Abstract

The essential focus of the present review is to collect the chemical reactions of chromone derivatives involving their transformation into coumarin derivatives. A diversity of coumarins was efficiently synthesized from the reactions of chromones with some nucleophilic reagents. This review includes the reactions of chromone derivatives with nitrogen and carbon nucleophiles, (acyclic and cyclic) leading to coumarins.

■ Synthetic Study of the C’D’E’ Ring System of Maitotoxin via Furan Based Strategy

Yuta Watanabe, Kohei Torikai, Yoko Yasuno, and Tohru Oishi*

*Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

Synthetic study of the C’D’E’ ring system of maitotoxin was examined via Suzuki–Miyaura coupling of an exo-iodoolefin and a furanylborane derivative, followed by Sharpless asymmetric dihydroxylation, Achmatowicz reaction, borylation/oxidation, and reductive etherification.

■ Synthesis and Biological Evaluation of New Pyrimidine Derivatives as FAK Inhibitors for Development of Antitumor Agents

Di Zhang, Qin Wang, Jing Yang, Qing Zhang, Yi Le, Li Liu, and Longjia Yan*

*School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China

Abstract

In this paper, a set of new pyrimidine derivatives was designed and synthesized. Subsequently, all the final targets were evaluated for antitumor activities in vitro on four human cancer cell lines including U-87 MG, MDA-MB-231, PC-3, and MCF-7, which were high expressed with focal adhesion kinase (FAK). The results were shown that these compounds performed well antitumor activities. Especially 2-((2-((4-((2-((2-acrylamidoethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (7b) exhibited the highest antitumor activities with 2.16 μM, 2.03 μM, 6.19 μM, and 21.31 μM, respectively. In addition, all the compounds were tested activities against FAK and compound 7b was also the best candidate with IC50 value of 5.9 nM.

■ Five New Compounds from Arenga pinnata (Wurmb.) Merr. Fruits

Ji-Fei Liu, Xin Cai, Feng-Jin Li, Chang Wang, Jin-Hai Huo,* and Wei-Ming Wang*

*Institute of Chinese Materia Medica, HeilongJiang Academy of Chinese Medicine Sciences, Harbin 150036, China

Abstract

Phytochemical investigation of Arenga pinnata (Wurmb.) Merr. fruits led to the isolation of 5 new compounds, designated A. pinnata A-E (1–5), and 13 known compounds (6–18). All compounds were isolated from A. pinnata for the first time. Their chemical structures were identified based on extensive spectroscopic methods, including HR-ESI-MS, 1D and 2D-NMR. To the best of our knowledge, this is the first systematic scientific study on the chemical composition of the Arenga genus.

■ Semi-Synthetic Chasmanthinine Analogues with Antifeedant Effects against Spodoptera exigua

Ziyu Song, Ke Xu, Jing Li, Yayun Xie, Xiang Li, Shuai Huang, Feng Gao, Lin Chen, and Xianli Zhou*

*School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, P. R. China

Abstract

The synthesis and structure modification of active natural lead compounds is an important approach for the discovery of novel green pesticides. Nineteen derivatives of chasmanthinine, a natural C19-diterpenoid alkaloids, were prepared, and their structures were unambiguously determined by 1H NMR, 13C NMR, and HR-ESI-MS. Moreover, the antifeedant activities of title compounds were evaluated against larvae of Spodoptera exigua (Hübner). The results illustrated that compounds p with a thienyl group at the C-14 position (EC50 = 0.10 mg/cm2) showed the strongest antifeedant activities among all tested compounds. This present study is the first report on the antifeedant effects of synthetic chasmanthinine analogs aganist S. exigua (Hübner) larvae.

■ Oscillatoxin E and Its C7 Epimer Show Distinct Growth Inhibition Profiles against Several Cancer Cell Lines

Yusuke Hanaki,* Yusuke Araki, Toshio Nishikawa, and Ryo C. Yanagita

*Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan

Abstract

Oscillatoxins (OTXs) are naturally occurring polyketides produced by some marine cyanobacteria. We have recently reported the total synthesis and in vitro biological activities of OTX-D, E, and F. Their spiro-ether structure was synthesized with an intramolecular Mukaiyama aldol reaction as a key step. Although the desired isomer was stereoselectively obtained, some amount of its C7 epimer was also produced as a byproduct. Using the C7 epimer, we investigated the effect of stereochemistry at the spiro-center of OTX-E (1) on its antiproliferative activity against several cancer cell lines. Growth inhibitory activity of 1 and its C7 epimer 2 was not strong, but they showed different efficacy profiles from each other. This result suggests that our synthetic method for OTXs would contribute to not only total synthesis of natural products but also to construction of chemical libraries containing unique biologically active compounds.

■ Efficient Synthesis of Cyclotriphosphazene Tripodal Tridentate Ligand via the Copper(I)-Template Method

Kazumasa Kajiyama,* Junpei Iwanami, and Hidetaka Yuge

*Division of Molecular Sciences, Graduate School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan

Abstract

An efficient synthesis of a cyclotriphosphazene tripodal tridentate ligand, cis,cis,cis-N/O trispirocyclic cyclotriphosphazene, via the copper(I)-template method was described. The reaction of hexachlorocyclotriphosphazene, N3P3Cl6, with 3 equiv of the dianion generated from 2-(1H-pyrazol-3-yl)phenol and NaH in THF in the presence of CuI afforded a copper(I) complex of the cyclotriphosphazene ligand in 51% yield. The solution of the complex in CH2Cl2 was treated with 25% NH3 aqueous solution to give the ligand in 82% yield. The 42% overall yield of the ligand via the complex starting from N3P3Cl6 was adequately improved compared to the yield of 8% in the reported synthesis of the ligand in the absence of CuI.

■ Inverted Positioning of DNMT1 Inhibitor in the Active Site of DNMT1 Caused by Hydrophobicity/Hydrophilicity of the Terminal Structure

Toshifumi Tojo,* Yuhei Kubo, Takeshi Kondo, and Makoto Yuasa

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

DNA (cytosine-5)-methyltransferase 1 (DNMT1) is one of the enzymes that regulate DNA modification. It has been demonstrated that overexpression of DNMT1 is associated with the development of cancer, making DNMT1 an attractive molecular target for cancer therapy. Focused on the terminal structures of existing DNMT1 inhibitors, we designed and screened test compounds that possessed another functional group. Binding simulations identified compounds with a trifluoromethylphenyl group to insert in an inverted position against DNMT1 compared to existing DNMT1 inhibitors. These results suggest that the binding form against DNMT1 may depend on the hydrophobicity/hydrophilicity of the inhibitor’s terminal structure.

■ Hybrid Linker Mode C2-Symmetrical 1,3,5-Triazine Derivatives and Their Biological Evaluation

Shunsuke Shimomura, Kazumi Yokomizo, Jian-Rong Zhou, Kaori Ota, Nobuko Mibu, Makoto Furutachi, and Kunihiro Sumoto*

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

Abstract

We report the preparation of some new multivalent hybrid-type C2-symmetrical molecules having a methylene linker group and 1,3,5-triazine (TAZ) moieties in the molecule and the results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. Some of the mid-sized C2-symmetrical multivalent hybrid-type molecules (3a) showed considerably high levels of anti-HSV-1 activity (EC50 = 28.8 ~ 32.0 μM) with low levels of cytotoxicity (CC50 = > 200 μM) against Vero cells. Among the tested hybrid-type TAZ derivatives, we reconfirmed that the hybrid-type C2-symmetrical multivalent molecule (3a-4) is an interesting candidate in the search for new hybrid-type multivalent mid-sized antiviral compounds.