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Published online: 24th June, 2022

Review | Regular issue | Prepress
DOI: 10.3987/REV-22-984
■ Gold-Catalyzed Skeletal Rearrangement Reactions of O-Propargylic and O-Homopropargylic Oximes

Itaru Nakamura* and Masahiro Terada

*Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Au-catalyzed skeletal rearrangement reactions of O-propargylic oximes, which were derived from the condensation of N-propargyloxyamine with either formaldehyde or glyoxylate, afforded the corresponding 4-methylenated isoxazolines via C=N bond cleavage. The obtained isoxazolines underwent carbonyl–ene reactions, generating functionalized isoxazoles in good yields. Moreover, a sequence of Au-catalyzed reactions followed by a carbonyl–ene reaction of enantioenriched substrate produced isoxazoles having a chiral side chain, with excellent levels of chirality transfer. In contrast, the Au-catalyzed reactions of O-propargylic oximes bearing an electron-deficient aryl group on the oxime carbon proceeded via N–O bond cleavage, affording oxazines in good yields.

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Published online: 21st June, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14679
■ Chemical Structures and Cell Death Inducing Activities of Constituents Isolated from Hibiscus tiliaceus

Takahiro Kitagawa, Takahiro Matsumoto,* Daisuke Imahori, and Tetsushi Watanabe*

*Public Health, Kyoto Pharmaceutical University, Shichonocho-1, Japan

Abstract

A new coumarin glycoside hibiscuscoumarin (1) was obtained with ten known compounds including seguinoside K (7) from the stems and twigs of Hibiscus tiliaceus. The structure of hibiscuscoumarin (1) was elucidated based on the chemical/physicochemical evidence. The cell death-inducing activities of the isolated compounds with or without Adriamycin (ADR) were observed using time-lapse cell imaging. The isolated compounds did not affect the number of mitotic entry cells and dead cells. Otherwise, the treatment of cells with seguinoside K (7) significantly increased the number of dead cells induced by ADR.

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Published online: 21st June, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14682
■ Silver-Catalyzed Conversion of CO2 and 2-Ethynylanilines into 4-Hydroxyquinolin-2(1H)-ones in Protic Ionic Liquid at Atmospheric Pressure

Qi Feng,* Keyan Yuan, Miaoqing Zhu, Jingzon You, and Congmin Wang

*Department of Science Education, Zhejiang International Studies University, No. 299, Liuhe Road, Zhejiang International Studies University, Hangzhou, Zhejiang, China

Abstract

4-Hydroxyquinolin-2(1H)-ones are core structural subunits frequently found in many pharmacological compounds and the synthesis of this kind of compounds is highly desirable. An efficient protic ionic liquid and AgNO3 catalytic system was developed for the preparation of various 4-hydroquinolin-2(1H)-ones from CO2 and 2-ethynylanilines in moderate to excellent yields (65-94%). It was found that [HTMG][Im], a simple and easily prepared protic ionic liquid comprising a 1,1,3,3-tetramethylguanidinium cation and a imidazolide anion, could act as both the solvent and reaction promoter, and that the reaction could be efficient carried out with a mount of 2 mol% AgNO3 under atmospheric pressure of CO2 at 60 ℃. This method provides a new approach for the synthesis of 4-hydroxyquinolin-2(1H)-ones.

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Published online: 21st June, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14692
■ Coniferains C and D, New Eunicellin-Based Diterpenoids from Cladiella conifera

Jhao-Syuan Zeng, Tung-Ying Wu, Po-Jen Chen, Wei-Chiung Chi, Nan-Fu Chen, Yang-Chang Wu, Lee-Shing Fang, Shun-Hua Chen,* Liang-Mou Kuo,* and Ping-Jyun Sung*

*Department of Planning and Research, National Museum of Marine Biology and Aquarium, 2 Houwan Road, Checheng, Pingtung, Taiwan 944, Taiwan

Abstract

Chemical examination of Cladiella conifera, collected in the waters of Taiwan, led to the isolation of two new eunicellin-based diterpenoids, coniferains C (1) and D (2). The structures of 1 and 2 were established by spectroscopic methods. Eunicellins 1 and 2 were found to promote cell viability in DLD-1 cells at a concentration of 20 μM.

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Published online: 20th June, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14689
■ Diversity-Oriented Synthesis of 2-Substituted Purine Nucleosides from Available Nucleosides via the Late-Stage Nitration/Derivatization

Ran Xia,* Li-Jie Liu, Chao Xia, Li-Ping Sun,* and Lei-Shan Chen*

*Department of Chemistry and Chemical Engineering, Xinxiang University, East of JinSui Road, XinXiang City, Henan Province, 453003, China

Abstract

A practical synthesis of 2-substituted purine nucleosides was developed in good to excellent yields from readily available nucleosides, such as adenosine, vidarabine and 2′-deoxyadenosine, via the late-stage nitration/derivatization. The C(2)-H bonds of purines were nitrated by 2,2,2-trifluoroacetic anhydride/Bu4NNO3, followed by nucleophilic substitution or hydrogenolysis reduction converting C(2)-NO2 to C(2)-Cl, C(2)-F, C(2)-N, C(2)-O and C(2)-S bonds. This system could tolerate arabinofuranosyl, ribosyl, deoxyribosyl, -OH or -NH2 groups. The clinical drugs, Regadenoson, Cladribine and Fludarabine, and the important naturally occurring nucleosides, spongosine and crotonoside, could be obtained successfully even on 20 g scales, which made this route more attractive for industrial applications.

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Published online: 14th June, 2022

Communication | Regular issue | Prepress
DOI: 10.3987/COM-22-14684
■ Microwave-Assisted Approach to Nitrobenzene/Aminepyridine and Its Inhibition Activity of Seed Germination

Zhi-you Huang,* Wen-sheng Li, Bo He, Ning Zhang, Zi-Ying Guo, Xiao-Hong Li, and Xian-Jun Yang

*College of Urban and Rural Construction, Shaoyang university, hunan province, China

Abstract

An efficient approach to nitroaniline/aminopyridine was developed under microwave irradiation. The sulphamide and halogenated nitrobenzene/pyridine were used as starting materials. With low consumption, environment friendly, gram-scale synthesis, good substrate scope and excellent product yields, this methodology is superior to the existing approach. Additionally, these compounds 3a-3s could inhibit soybean seed germination at the concentration of 50 µM. Especially, the inhibition rate of compound 3m was higher than 90%.

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Published online: 10th June, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14680
■ Briarane-Type Diterpenoids from the Cultured Octocoral Briareum stechei (Kükenthal, 1908)

You-Ying Chen, San-Nan Yang, Zhi-Hong Wen, Su-Ying Chien, Jih-Jung Chen, Jui-Hsin Su, Chia-Ching Liaw, Yu-Chi Tsai,* and Ping-Jyun Sung*

*Department of Planning and Research, National Museum of Marine Biology and Aquarium, 2 Houwan Road, Checheng, Pingtung, Taiwan 944, Taiwan

Abstract

A known briarane, excavatolide E (1), along with three previously unreported briaranes, briastecholides D–F (2–4), were purified from an aquacultured form of octocoral Briareum stechei. Spectroscopic approaches were first used to reveal the structures of newly-identified briaranes 2–4; single-crystal X-ray analysis was then performed to identify the absolute configuration of 1. To characterize their biological functions, an anti-inflammatory assay using macrophage cell line RAW264.7 as an in vitro model was employed. The results of the assay showed that briarane 1 prevented the protein production of pro-inflammatory inducible nitric oxide synthase (iNOS) in macrophages caused by lipopolysaccharide stimulation.

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Published online: 30th May, 2022

Review | Regular issue | Prepress
DOI: 10.3987/REV-22-982
■ Non-Planar Polycyclic Aromatic Molecules Including Heterole Units

Koki Kise and Takayuki Tanaka*

*Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Abstract

Recent developments in non-planar polycyclic aromatic molecules bearing heterole units have been reviewed, including internally and externally heteroatom doped corannulenes, rim and benzylic heteroatom doped sumanenes, hexapyrrolohexaazacoronenes, and hetero[n]circulenes.

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Published online: 27th May, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-22-14667
■ New Bioactive Sesquiterpenoid from Malaysian Soft Coral Genus Lemnalia

Kazuki Tani, Takashi Kamada, Chin-Soon Phan, and Charles S. Vairappan*

*Laboratory of Natural Products Chemistry, Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, 88400 Kota Kinabalu, Sabah, Malaysia

Abstract

One new sesquiterpenoid, parathyrsoidin K (1) along with seven known related secondary metabolites, parathyrsoidin J (2), lemnal-1(10)-ene-7β,12ζ-diol (3), linardosinene C (4), paralemnolin J (5) and K (6), 1S*,4S*,5S*,10R*-4,10-guaianediol (7), and 4-acetoxy-2,8-neolemnadien-5-one (8), were isolated from the organic extracts of soft coral Lemnalia sp. Their structures were elucidated based on spectroscopic analyses and these compounds were evaluated to anti-inflammatory activity against lipopolysaccharide-stimulated RAW 264.7 macrophages and antifungal activity against seven fungal strains.

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Published online: 23rd May, 2022

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)15
■ Synthesis of Penicolinates A, C and D

Angela Qi Yun Chiu, Krishna Ramesh, Ma Yadanar Phyo, Patcharaporn Sae-Lao, and Roderick Wayland Bates*

*Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371

Abstract

Penicolinates A, C and D are synthesized using the Sonogashira coupling reaction as a key step. By comparison of the optical rotation, the stereochemistry of penicolinate D is determined to be (S).

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Published online: 20th May, 2022

Communication | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)22
■ Synthesis of Benzo[d]pyrrolo[1,2-a]imidazoles by Iminocyclopropane Rearrangement of C-Cyclopropylbenzimidazoles

Adam P. Montoya, Matthew G. LaPorte, and Peter Wipf*

*Department of Chemistry, University of Pittsburgh, Pittsburgh PA 15260, USA

Abstract

The MgI2 or NH4I mediated iminocyclopropane rearrangement of trisubstituted acrylonitrile benzimidazoles provides an attractive access to novel pyrrolo[1,2-a]imidazoles. The rearrangement precursors, C-cyclopropylbenzimidazoles, are obtained by a Corey-Chaykovsky cyclopropanation of the acrylonitrile. We determine the scope of the iminocyclopropane rearrangement to 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-carbonitrile and 2,4-dihydro-2,4-disubstituted as well as 1,2,4-trisubstituted 1H-benzo[d]pyrrolo[1,2-a]imidazole-3-carbonitriles, and describe some of the limitations and side reactions, including the formation of aromatized 4H-benzo[d]pyrrolo[1,2-a]imidazole-3-carbonitriles.

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Published online: 9th May, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)19
■ N-Heterocyclic Analogs of Indenocorannulene

Ansu Li, Jun Xu, Kim K. Baldridge, and Jay S. Siegel*

*School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China

Abstract

Four chiral N-heterocyclic monoindenocorannulenes were prepared by fusing pyridine, quinoline, and indole across the peri-positions of corannulene via tandem Suzuki-aryl-aryl coupling and C-Cl activated ring closure reactions. The UV-Vis, fluorescence, and CV properties of these N-doped polynuclear aromatics are discussed. Resolution of enantiomers is performed on chiral stationary phase HPLC and the absolute configurations are assigned by comparison of experimental and quantum mechanically predicted ECD spectra.

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Published online: 27th April, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)8
■ Sparsomycin – a Review and Re-assessment

Geoffrey A. Cordell* and Sharna-kay Daley

*Natural Products Inc., Evanston, IL, 60202, U.S.A.

Abstract

The chemistry, biology, and biosynthesis of the microbial alkaloid sparsomycin (1) are summarized and re-assessed to identify future research initiatives for this biologically significant metabolite.

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Published online: 26th April, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)20
■ Synthesis of 1-Azaspiro[4,5]-7-decen-2-one from L-Asparagine and L-Aspartic Acid

Punlop Kuntiyong,* Sunisa Moongmai, Natida Thongluar, and Ittiphat Klayparn

*Department of Chemistry, Faculty of Science, Silpakorn University, Sanamchandra Palace, Muang Nakhon Pathom 73000, Thailand

Abstract

A synthetic strategy for 1-azaspiro[4.5]-7-decen-2-one based on N-acyliminium spirocyclization is reported. The common core structure found in biologically active alkaloids such as FR901483, TAN1251 and lepadiformine was synthesized via chiral N-alkyl-3-dibenzylaminosuccinimide intermediates. The chiral succinimides were synthesized in 2 steps from L-aspartic acid or 3 steps from L-asparagine.

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Published online: 25th April, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)17
■ 2-Arylazoimidazoles Revamped by Quarternization or Dimerization; Another Gain in Functionality of an Industrial Dyestuff Family by Task-Specific Side-Chain Substituents

Sandro Neuner, Heidi A. Schwartz, Christoph Kreutz, Thomas Müller, Paul Mayer, Günther Bonn, Thomas Gelbrich, Ulrich J. Griesser, Klaus Wurst, Volker Kahlenberg, Sven Nerdinger,* and Herwig Schottenberger*

*Sandoz GmbH, Biochemiestr. 10, 6250 Kundl, Austria

Abstract

Based on [(E)-2-(4-fluorophenyl)diazenyl]-1H-Imidazole,[210180-24-0], a versatile late stage intermediate for the divergent synthesis of direct dyes, a novel series of N,N`-disubstituted azoimidazolium salts was prepared. In particular, benzylation, 4-vinylbenzylation, phenacylation, sulfopropylation, ethylation, as well as propargylation allowed for the access of derivatives (1-6), which are useful for follow-up conversions, e.g. click reactions, or free radical polymerization. The compounds were routinely characterized spectroscopically. The diethylated tetrafluoroborate salt 5 was additionally analyzed by 19F-NMR. Hot stage microscopy of contact melts of 5 with the less commonly used anionic nucleophiles azide and rhodanide illustrate the rapid formation of deeply colored products confirming the nucleophilic aromatic replacement of fluoride in the 4-fluorophenyl substituent. Remarkably, in addition to the conceived functional quarternizations, a neutral dimer chromophore (7) resulted from using epichlorohydrin as a linking agent. Single crystal X-ray structure determinations are reported for all newly described compounds.

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Published online: 14th April, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)13
■ Synthesis of Novel Fluorescent Bicyclic Amidines and Evaluation of Their Photophysical Properties

Wannaporn Disadee,* Kittiporn Trisupphakant, and Somsak Ruchirawat

*Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Lak Si, Bangkok 10210, Thailand

Abstract

A metal-free process for the synthesis of novel bicyclic amidines was developed. The key conversions involved a cascade of double intramolecular cyclization of Michael adducts under a mild condition to provide 39 analogs in up to 93% yield. Photophysical properties of the representatives, a parent molecule and its free base form were studied on different solvents. From the results, a free base form exhibited strong fluorescent emission wavelength in up to 491 nm and large Stoke shift in up to 140 nm, offering positive information for their future development.

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Published online: 14th April, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)9
■ The Xanthate Route to Benzazepinones and Their Aza Congeners

Béatrice Quiclet-Sire and Samir Z. Zard*

*Department of Chemistry, Ecole Polytechnique, CNRS UMR 7652, 91128 Palaiseau, France

Abstract

The present brief overview highlights and discusses the synthetic potential of the degenerative radical addition of xanthates for the synthesis of benzazepinones and their aza congeners. Various routes are presented, including direct cyclisations onto the aromatic or heteroaromatic ring, intermolecular radical additions followed by ring closure, and Beckmann ring expansion of tetralones produced by radical addition-cyclisation. Many of the compounds described are medicinally relevant and not readily available by more conventional methods.

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Published online: 12th April, 2022

Communication | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)18
■ Synthesis and Stereochemical Analysis of Planar Chiral Nine-Membered Aza-Orthocyclophyne

Yuuya Kawasaki, Sumire Tanaka, Kazunobu Igawa, and Katsuhiko Tomooka*

*Institute for Materials Chemistry and Engineering, Department of Molecular and Material Sciences, and IRCCS Kyushu University, Kasuga, Fukuoka 816-8580, Japan

Abstract

Aza-orthocyclophyne 3b with an oxy-substituent on the 16 position of the benzene ring was synthesized, and it was revealed that the stereochemical stability of 3b is consistent with the order of 1,3-steric repulsion between the C2 methylene protons and the oxy-substituent.

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Published online: 12th April, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)21
■ Oxidative Fragmentation of Cytisine as an Entry to the Bis(piperidine) Scaffold of Virgidivarine

Worawat Niwetmarin* and Timothy Gallagher*

*School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom

Abstract

Using virgidivarine as a focus, we have extended the oxidative fragmentation of (-)-cytisine as a source of functionalized heterocyclic fragments to provide a novel bis(piperidine) 2′-epivirgidivarine. This stereochemically-defined scaffold offers synthetic versatility within an “sp3-rich” environment that makes it amenable to further manipulation and development within the context of de novo drug design.

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Published online: 7th April, 2022

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)14
■ Synthesis and Cytotoxic Activity of Wrightiadione and Its Derivatives

Sanit Thongnest and Jutatip Boonsombat*

*Chulabhorn Research Institute, Bangkok 10210, Thailand

Abstract

A synthetic method for generating the tetracyclic isoflavone wrightiadione was developed through a Friedel-Crafts acylation of isoflavone-2-carboxylic acid. A series of wrightiadione derivatives was conveniently synthesized by this approach and evaluated for cancer cytotoxic, cancer chemopreventive, and antimalarial properties. Some derivatives exhibited potent cancer cytotoxic activity at the single-digit micromolar level.

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Published online: 6th April, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)7
■ Five-Membered Nitrogen Heterocycles as New Lead Compounds in Drug Discovery

Agustono Wibowo, Mohd Fazli Mohammat, Zurina Shaameri, Fatin Nur Ain Abdul Rashid, Noor Hidayah Pungot, and Ahmad Sazali Hamzah*

*Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia

Abstract

Five-membered nitrogen heterocyclic compounds are a very important group with various pharmaceutical properties. The different substitutions and functionalization of these compounds contributed to various biological activities. Five-membered nitrogen heterocyclic scaffolds are used for synthesizing numerous natural and synthetic compounds with a significant biological application. They include antidiabetic, anticancer, antimalarial, antiviral, antimicrobial, anti-inflammatory, antibacterial, and anti-neurodegenerative agents. This mini-review provides an overview of the biological activities and the synthetic methods for preparing the five-membered nitrogen heterocyclic scaffolds and their functionalization. In the final part, this mini-review also listed some commercial drugs containing five-membered nitrogen heterocyclic motifs, highlighting the versatility of the five-membered nitrogen heterocyclic core in drug discovery.

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Published online: 5th April, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)6
■ 8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

Veda Prachayasittikul,* Ratchanok Pingaew, Supaluk Prachayasittikul, and Virapong Prachayasittikul

*Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

Abstract

8-Hydroxyquinoline (8HQ) is an attractive heterocyclic scaffold with well-known metal chelating property, broad-ranging pharmacological activities, and preferrable drug-likeness, thus, it had gained a continual attention in areas of drug development, especially, drug repurposing. Alzheimer’s disease (AD) is one of globally health concern in an era of aging society and its management is considered challenging as effective disease-modifying drugs are still clinically unavailable. Loss of metal ion homeostasis is one of key factors contributing to pathogenesis and progression of AD in which its imbalance could trigger many related key factors and harmful events, especially, oxidative neuronal damages. Hence, restoration of homeostasis and distribution of brain’s metal ions served to be a promising strategy for development of disease-modifying agents. In this review, essential key points relating to AD pathogenesis, roles of metal ions in AD, and pioneer 8HQ-based compounds are introduced. A series of recently reported 8HQ-based neuroprotective compounds (i.e., derivatives, hybrids, conjugates, and metal complexes) focusing on compounds acting as metal chelators are reviewed. Related 8HQ-based neuroprotective compounds with other mechanisms of actions are also discussed. Additionally, summary of key contents is included to provide an overview of current development situations. Taken together, this article would be beneficial and inspiring for the related future drug design and development to tackling an increasing prevalence of neurodegenerations in the global aging society.

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Published online: 1st April, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)4
■ 1,2,3-Triazole Scaffold in Recent Medicinal Applications: Synthesis and Anticancer Potentials

Vanida Choomuenwai,* Ronnakorn Leechaisit, Ratchanok Pingaew,* Veda Prachayasittikul, Supaluk Prachayasittikul, and Virapong Prachayasittikul

*Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand

Abstract

Cancer is one of commonly concerned health problems globally and its management is challenging. Besides an availability of diverse classes of anticancer agents, the existing drugs are noted for their limitations such as considerable toxicities, low potency and responsiveness, drug resistance, and others. 1,2,3-Triazole is an attractive heterocyclic scaffold possessing considerable characteristics and is presented in many pharmacologically active molecules. Accordingly, attention has been given to this scaffold in the recent years, especially, in an area of anticancer drug development. In this review, a collection of recently reported triazole based anticancer agents are discussed along with their synthetic methods, proposed molecular targets, and mechanisms of actions. A summary of other recently reported biological activities is also provided. In overview, recent studies suggested that the 1,2,3-triazole based compounds could elicit their anticancer effects against several cancer cell lines via an inhibition of cancer cell growth, an induction of apoptosis, an inhibition of involved enzymes such as aromatase, kinases, and others. Some interesting results from computational studies also discussed relating to the predictions of possible molecular targets. In summary, it is suggested that the 1,2,3-triazole serves as a potential scaffold with noteworthy opportunity for future development of novel anticancer agents to cope with current challenging issues in cancer management.

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Published online: 1st April, 2022

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)12
■ Asymmetric Intramolecular Aldol Reactions Mediated by Chiral Triamines Bearing a Pyrrolidine Scaffold to Provide a Wieland–Miescher Ketone

Yuichi Akahane and Kohei Inomata*

*Department of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara 324-8501, Japan

Abstract

We established a new asymmetric route to provide (R)-Wieland–Miescher ketone [(R)-2] using a combination of trifluoroacetic acid (TFA) and known or new chiral triamines (7) bearing a pyrrolidine scaffold. Although the intramolecular aldol reaction of trione (1) mediated by chiral prrolidine (7) resulted in the production of 2 with low enantioselectivities, a remarkably increased enantioselectivity with a combination of 7b or 7c and TFA was observed. We also found that a secondary amine motif existing in the middle of the side chain was important in defining the enantioselectivity.

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Published online: 31st March, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)11
■ Novel Synthesis and Properties of Optically Pure N-Trifluoroacetylphenylglycine Hydroxysuccinimide Ester

Zeping Wang, Shoko Ishikawa, Fumina Ohashi, Reo Sagisaka, Yuta Murai, Zetryana Puteri Tachrim, Takeyuki Suzuki, and Makoto Hashimoto*

*Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-ku, Sapporo, Hokkaido, Japan

Abstract

Phenylglycine is non-proteinogenic α-amino acid, and its partial structure is found in some biologically active compounds. C-Terminal modification of N-acyl-protected phenylglycine sometimes causes racemization due to the fact that the phenyl ring is directly connected to the α-position of the α-amino acid skeleton. In this report, synthesis and the property of N-trifluoroacetylphenylglycine hydroxysuccinimide ester was archived.

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Published online: 28th March, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-21-SR(R)2
■ The Utility of Oxoammonium Species in Organic Synthesis: Beyond Alcohol Oxidation

Shota Nagasawa, Yusuke Sasano, and Yoshiharu Iwabuchi*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

Abstract

Oxoammonium species are electrophilic chemical species generated via single electron oxidation of nitroxyl radicals. Although this species and its salts are known as useful oxidants and active species for (catalytic) oxidation of alcohols into carbonyl compounds in organic synthesis, the benefits of oxoammonium species for the oxidative transformations of numerous types of substrates apart from alcohols has been reported. This review summarizes the synthetic utility of oxoammonium species under both stoichiometric and catalytic conditions with the exception of alcohol oxidation.

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Published online: 24th March, 2022

Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)16
■ Construction of Tetrahydroquinolines with Spirocyclic Structures at the 4-Position

Yuko Wakahara, Takahiro Noro, Juri Sakata, Hirofumi Ueda, and Hidetoshi Tokuyama*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan

Abstract

The construction of tetrahydroquinolines with a spirocyclic structure at the 4-position was studied. The five-step sequence includes construction of benzocyclopentanone oxime by Knoevenagel condensation of cyclic ketones with Meldrum’s acid followed by Michael addition of aryl Grignard Reagent, intramolecular Friedel–Crafts acylation, condensation with hydroxylamine, and reductive ring expansion reaction using diisobutylaluminium hydride. The utility of this method was demonstrated by construction of a variety of tetrahydroquinolines possessing a four to eight-membered spirocyclic ring as well as adamantane and indane structures at the 4-position.

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Published online: 8th March, 2022

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)9
■ Improved Synthesis of Naldemedine Tosylate and Crystal Structures of Four Related Solid Forms

Josef Spreitz, Thomas Gelbrich, Sven Nerdinger,* Marijan Stefinovic, and Ulrich J. Griesser

*Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

The production of drug substances requires a robust and scalable process capable of delivering the active pharmaceutical ingredient (API) in excellent chemical and polymorphic purity. With this goal in mind we have developed an improved procedure for the preparation of naldemedine tosylate, which crystallizes directly from the reaction mixture as pure polymorph form II. Solid state studies revealed a series of additional new physical forms whose crystal structure have been determined by single-crystal X-ray diffraction.

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Published online: 8th March, 2022

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-22-S(R)10
■ Synthesis of N3-Substituted Quinazoline-2,4-diones via C-4 Amination-Cyclization of Isatoic Anhydrides

Nittaya Wiriya, Dolnapa Yamano, Surat Hongsibsong, Mookda Pattarawarapan, and Wong Phakhodee*

*Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

Abstract

A direct approach for the synthesis of N3-substituted quinazoline-2,4-diones via condensation of isatoic anhydrides with amines mediated by Ph3P-I2 was reported. Instead of the expected benzoxazinones, the reaction proceeds with an amine attack at the C-4 position of isatoic anhydrides leading to quinazoline-2,4-diones upon heating in the presence of base. This one-pot process enables a rapid construction of a broad range of quinazoline-2,4-dione derivatives using simple, readily available, and low-cost reagents with no extra carbonylating agent needed.

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Published online: 7th March, 2022

Review | Special issue | Prepress
DOI: 10.3987/REV-22-SR(R)5
■ Heterocyclic Stilbene and Bibenzyl Derivatives in Liverworts: Distribution, Structures, Total Synthesis and Biological Activity

Yoshinori Asakawa* and Fumihiro Nagashima

*Institute of Pharmacognosy, Tokushima Bunri University, Tokushima 770-8514, Japan

Abstract

Liverworts are a rich source of lipophilic terpenoids, and aromatic compounds especially bibenzyl and bis-bibenzyl derivatives. This review is concerned with the distribution of heterocyclic stilbenes and bibenzyls in liverworts, belonging to the Acrobolbaceae, Aytoniaceae, Frullaniaceae, Lejeuneaceae, Plagiochilaceae, and Radulaceae families. Some Radula species elaborate bibenzyl cannabinoids, which possess remarkably similar biological activity to that of the Δ9-tetrahydrocannabinoids, the psycho- and anti-inflammatory active metabolites found in Cannabis sativa.

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