1-Deoxynojirimycin: Occurrence, Extraction, Chemistry, Oral Pharmacokinetics, Biological Activities and in Silico Target Fishing
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molecules Review 1-Deoxynojirimycin: Occurrence, Extraction, Chemistry, Oral Pharmacokinetics, Biological Activities and In Silico Target Fishing Kuo Gao 1,†, Chenglong Zheng 1,2,†, Tong Wang 2, Huihui Zhao 1, Juan Wang 1, Zhiyong Wang 1, Xing Zhai 1, Zijun Jia 1, Jianxin Chen 1, Yingwu Zhou 2,* and Wei Wang 1,* 1 Beijing University of Chinese Medicine, Bei San Huan East Road, Beijing 100029, China; [email protected] (K.G.); [email protected] (C.Z.); [email protected] (H.Z.); [email protected] (J.W.); [email protected] (Z.W.); [email protected] (X.Z.); [email protected] (Z.J.); [email protected] (J.C.) 2 Beijing Gulou Hospital of Traditional Chinese Medicine, 13 DouFuChi Hutong, Dongcheng District, Beijing 100009, China; [email protected] * Correspondence: [email protected] (Y.Z.); [email protected] (W.W.); Tel.: +86-10-6401-2858 (Y.Z.); +86-10-6428-7452 (W.W.) † These authors contributed equally to this work. Academic Editor: Derek J. McPhee Received: 13 October 2016; Accepted: 16 November 2016; Published: 23 November 2016 Abstract: 1-Deoxynojirimycin (DNJ, C6H13NO4, 163.17 g/mol), an alkaloid azasugar or iminosugar, is a biologically active natural compound that exists in mulberry leaves and Commelina communis (dayflower) as well as from several bacterial strains such as Bacillus and Streptomyces species. Deoxynojirimycin possesses antihyperglycemic, anti-obesity, and antiviral features. Therefore, the aim of this detailed review article is to summarize the existing knowledge on occurrence, extraction, purification, determination, chemistry, and bioactivities of DNJ, so that researchers may use it to explore future perspectives of research on DNJ. Moreover, possible molecular targets of DNJ will also be investigated using suitable in silico approach. Keywords: iminosugar; mulberry; Bacillus; fermentation; silkworms; antihyperglycemic; anti-obesity; antiviral; molecular targets 1. Introduction Polyhydroxylated piperidines and their derivatives are famous for their excellent bioactivities [1]. Iminosugars contain an analog of pyranose ring or D-glucose, in which the ring oxygen atom is replaced by a nitrogen atom. 1-Deoxyiminosugars are chemically more stable than normal iminosugars because of absence of a hydroxyl group at the C1 position. Among the iminosugars, naturally occurring 1-deoxyiminosugars such as DNJ are strong glycosidase inhibitors [2]. Originally, reduction of nojirimycin led to the chemical synthesis of DNJ [3]; afterward, DNJ was found from natural source, i.e., mulberry tree root and Bacillus species [4,5]. 1-Deoxynojirimycin (DNJ, C6H13NO4, 163.17 g/mol) (Figure1), an alkaloid azasugar or iminosugar, is a biologically active natural compound [6–8]. The IUPAC name of DNJ is (2R,3R,4R,5S)- 2-(hydroxymethyl)piperidine-3,4,5-triol. It is also known as moranoline [9]. Various derivatives of DNJ are N-azidopropyl-1-deoxynojirimycin, N-nonyl-1-deoxynojirimycin, 1-deoxynojirimycin-6- phosphate, and N-methyl-1-deoxynojiri-mycin-6-phosphate [8]. It exists in mulberry leaves and Commelina communis (dayflower) as well as from several bacterial strains such as Bacillus and Streptomyces species [7]. Molecules 2016, 21, 1600; doi:10.3390/molecules21111600 www.mdpi.com/journal/molecules Molecules 2016, 21, 1600 2 of 15 Molecules 2016, 21, 1600 2 of 14 Figure 1. Chemical structure of 1-Deoxynojirimycin [7]. Figure 1. Chemical structure of 1-Deoxynojirimycin [7]. AfterAfter extraction, extraction, DNJDNJ contents contents can can be determin be determineded by HPLC by using HPLC various using detectors various such detectors as suchfluorescent, as fluorescent, evaporative evaporative light-scattering light-scattering detector, pulsed detector,amperometric, pulsed and Mass amperometric, spectrometer [10–12]. and Mass spectrometerSince DNJ [ molecule10–12]. Since does not DNJ contain molecule chromophore, does not the contain quantification chromophore, of DNJ through the quantification spectral analysis of DNJ needs derivatization, i.e., an analytical approach for quantification of nitrogen-containing compounds through spectral analysis needs derivatization, i.e., an analytical approach for quantification of [13–16]. To quantify and resolve structural information of DNJ by GC-MS, Bajpai and Rao used nitrogen-containing compounds [13–16]. To quantify and resolve structural information of DNJ trimethylsilyl (TMS) derivatization [7]. by GC-MS,The Bajpai pharmacokinetic and Rao used of DNJ trimethylsilyl after oral administrati (TMS)on derivatization has been studies [7]. by some researchers [17–19]. TheMoreover pharmacokinetic, DNJ has many of biological DNJ after activities, oral administration including antihyperglycemic has been studies [20–25], by some anti-obesity researchers [26–30],[17 –19]. Moreover,and anti-viral DNJ has [31] many have biological also been activities,reported [32–35]. including antihyperglycemic [20–25], anti-obesity [26–30], and anti-viralCurrently, [31] havethe prediction also been of biological reported targets [32–35 of]. small drug molecules has become very easy owing Currently,to the rapid the growth prediction of bioactivity of biological databases, targets in silico of small target drug fishing molecules approaches has become and accessible very easy web owing to theservices rapid [36]. growth There of are bioactivity many approaches databases, to in in silico silico target target fishing fishing including approaches the structure-based and accessible and web servicesthe ligand-based [36]. There aremethods, many data approaches mining, and to inchemical silico targetsimilarity fishing searching including [37]. Then, the structure-based the output data and of these approaches are validated by adopting useful modality. The structure-based target prediction the ligand-based methods, data mining, and chemical similarity searching [37]. Then, the output data methods are appropriate to the drug-like small organic entities, which induce biological effects but of these approaches are validated by adopting useful modality. The structure-based target prediction have ambiguous macromolecular targets [36]. methodsTherefore, are appropriate the aim to of the this drug-like detailed review small organicarticle is entities,to summarize which the induce existing biological knowledge effects on but haveoccurrence, ambiguous extraction, macromolecular purification, targets determination, [36]. chemistry, and bioactivities of DNJ, so that the Therefore,researchers may the use aim it ofto explore this detailed future perspectives review article of research is tosummarize on DNJ. Moreover, the existing possibleknowledge molecular on occurrence,targets of extraction, DNJ will also purification, be investigated determination, using suitable chemistry, in silico approach. and bioactivities of DNJ, so that the researchers may use it to explore future perspectives of research on DNJ. Moreover, possible molecular targets2. 1-Deoxynojirimycin of DNJ will also be investigated using suitable in silico approach. 2. 1-Deoxynojirimycin2.1. Occurrence 1-Deoxynojirimycin (DNJ), a product of fermentation, exists in mulberry leaves and 2.1. OccurrenceCommelina communis (dayflower) as well as is isolated from several bacterial strains such as Bacillus and Streptomyces species [7,8]. Mulberry, a common deciduous plant, belongs to the genus Morus (Moraceae 1-Deoxynojirimycin (DNJ), a product of fermentation, exists in mulberry leaves and family). The botanical and pharmaceutical names of mulberry tree are Morus alba L. and Folium mori, Commelina communis (dayflower) as well as is isolated from several bacterial strains such as Bacillus respectively [38]. Mulberry tree is found in countries with a subtropical or mild temperate environment, and Streptomycesincluding China,species Japan, [ 7Korea,,8]. Mulberry, India, Pakistan, a common and other deciduous Asian countries plant, [39]. belongs By reason to the of genus folkloreMorus (Moraceaetonic, mulberry family). leaves The botanical have been and used pharmaceutical as an anti-diabetic names tea. The of mulberrygeneral use tree of mulberry are Morus includes alba L. and Foliumsilkworm mori, respectively (Bombyx mori [ 38L.)]. feeding Mulberry (Figures tree 2 isand found 3) [40], in fruit countries production with [41], a subtropical and medicine or preparation mild temperate environment,[42,43]. Mulberry including leaves China, are used Japan, as Korea,a source India, of protein Pakistan, in food and products other Asian[44]. Many countries scientific [39 studies]. By reason of folklorehave reported tonic, mulberry the medicinal leaves importance have been of usedmulberry as an [45]. anti-diabetic Mulberry leaves tea. The are traditionally general use used of mulberry as includesmedicine silkworm for controlling (Bombyx blood mori L.) sugar feeding level [20,46–48]. (Figures2 andStudies3)[ have40], also fruit reported production the effectiveness [41], and medicine of preparationmulberry [ 42leaves,43]. in Mulberry skin aging leaves[49,50] and are neurodegenerative used as a source disorders of protein including in food Alzheimer’s products disease [44]. Many and Parkinson’s disease [51]. Moreover, sedative effect of mulberry fruits and anti-inflammatory, scientific studies have reported the medicinal importance of mulberry [45]. Mulberry leaves are diuretic, antitussive, and antipyretic properties of mulberry root bark have been studies [52]. In addition traditionally used as medicine for controlling blood sugar level [20,46–48]. Studies have also reported to DNJ, many other