DOI: 10.1515/cipms-2016-0008 Curr. Issues Pharm. Med. Sci., Vol. 29, No. 1, Pages 33-38 Current Issues in Pharmacy and Medical Sciences Formerly ANNALES UNIVERSITATIS MARIAE CURIE-SKLODOWSKA, SECTIO DDD, PHARMACIA journal homepage: http://www.curipms.umlub.pl/ Furochinoline alkaloids in plants from Rutaceae family – a review Aldona Adamska-Szewczyk1*, Kazimierz Glowniak2, Tomasz Baj2 1 Hibiscus Pharmacy, 26 Puławska Str, 02-512 Warszawa, Poland 2 Department Pharmacognosy with Medical Plant Unit, Medical University of Lublin, 1 Chodzki , 20-093 Lublin, Poland ARTICLE INFO ABSTRACT Received 17 November 2015 Over the past five years, phytochemical and pharmacological studies have been Accepted 11 January 2016 conducted on material extracted from members of the Rutaceae family. In such work, Keywords: new furochinoline-structured alkaloids were isolated from Ruta sp. and Dictamnus sp. Rutaceae, Beyond the aforementioned, other substances with promising activity were isolated furochinoline alkaloids, from the less-known species of Zanthoxylum, Evodia, Lonchocarpus, Myrthopsis and dictamnine, used forms of extraction, as well as methods of isolation and detection, skimmianine, Teclea. Currently kokusaginine, allow the obtaining of pure, biologically active compounds. Many of these have anti- activity, fungal, anti-bacterial and anti-plasmodial properties. Others are still being researched as Zanthoxylum, potential drugs, which, in future, may be used in treating those afflicted with HIV and Evodia, cancer. This article is designed to give the readers a thorough review of the active natural Conchocarpus, Myrthopsis, products from the Rutaceae family. Teclea. INTRODUCTION The Rutaceae family has about 140 genera [6], consisting albus L. These researchers examined this substance via the of herbs, shrubs and small trees which grow in all parts tracer method, and determined the quinoline nucleus from of the world [28,29,38], and which are used in traditional acetate and from anthranilic acid. Between 2010 and 2015, medicine for treating snake bites, stomatitis, rheumatism, further studies have been conducted which revealed new bronchitis and other diseases [28]. This plant family is alkaloid substances with the furochinoline structure. These the source of furanocoumarines, furochinoline alkaloids, alkaloids are a group of substances characteristic for the phenolic-structured compounds, terpens and other Rutaceae family (Fig. 1). substances [12,25,27]. The main alkaloid compounds drawn CH3 from this family are dictamnine (1), skimmianine (2) and O kokusaginine (13). In pharmacy, the most-known species of Rutaceae family are Ruta graveolens L. and Ruta montana Mill. The latter plant, and the substances isolated from O it, were subject to Nuclear Magnetic Resonance (NMR) R1 N research by Vasudevan & Luckner, in 1968 [33]. From the R2 whole plant, they extracted and examined six alkaloids: No. Compound R1 R2 2-(nonan-8-one)-(1H)-4-quinolone, 2-(nonan-8-one)-4- 1 Dictamnine –H –H methoxy-quinoline, 2-(nonan-8-one)-N-methyl-4-quinolone, 2 Skimmianine – OCH3 –OCH3 2-(decan-9-one)-N-methyl-4-quinolone, evolitrine (6) and 3 γ-Fagarine H – OCH3 1-methyl-4-methoxy-2-quinolone [32]. The most thoroughly 4 Haplopine – OH – OCH3 examined compound is dictamnine (1). This is the first 5 7-hydroxydictamnine – OH – H alkaloid isolated from this plant. In 1967, Moncović et al. 6 Evolitrine – OCH3 – H [21] presented the biosynthesis of dictamnine in Dictamnus * Corresponding author e-mail: [email protected] © 2016 Medical University of Lublin. This is an open access article distributed under the Creative Commons Attribution-NonComercial-No Derivs licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) 33 Furochinoline alkaloids in plants from Rutaceae family – a review Aldona Adamska-Szewczyk, Kazimierz Glowniak, Tomasz Baj Furochinoline alkaloids in plants from Rutaceae family – a review O Another approach to alkaloid extraction was presented R1 by Resmi et al., in the investigation of a type III polyketide synthase involved in the quinolone alkaloid biosynthesis of N O material obtained from Aegle marmelos (L.) Correa. This R 2 CH3 work was the first report of a gene being involved in qui- nolone biosynthesis as seen in plant material. Quinolone No Compound R1 R2 synthase, which is a type III polyketide synthase, was shown 7 Isodictamnine – H – H to synthesize diketide 4-hydroxy-1-methyl-2H-quinolone, 8 Isomaculosidine – OCH – OCH 3 3 by utilizing a unique substrate binding site [26]. 9 Iso-γ-fagarine – H – OCH3 10 Dictangustine-A – OH – H Sichaem et al. [29], while conducting pharmacognostic studies of new substances in the leaves of Evodia lepta 11 Isopteleine – OCH3 – H (Spreng.) Merr., isolated 3 leptanoines A-C (15-17), Figure 1. The structures of the main furoquinoline alkaloids melineurine (18), dictamnine (1) and 7-hydroxydictamnine isolated from plants of the Rutaceae family (5). In their work, the dried leaves of the plant underwent Extraction of furoquinoline alkaloids from Rutaceae extraction twice with 5 liters of methanol, at room family plants temperature. The result was then subjected to evaporation, supra, VLC (vacuum-liquid chromatography) and silica Sandjo et al. [28] isolated furoquinoline alkaloids from gel chromatography. The subsequent elution process was Zanthoxylum buesgenii (Engl.) P.G.Waterman, using completed by the use of solvents of increasing polarity in Dragendorff´s method. In this work, dried aerial plant the following order: dichloromethane, ethyl acetate and material was first cut into small pieces, then crushed, and the methanol. Four fractions were obtained, of which, one was powder underwent extraction for two days, using methylene subjected to column chromatography with dichloromethane, chloride (DCM)/MeOH (1:1 v/v). The solid residue was yielding several sub-fractions. One of these was purified subsequently extracted with MeOH. After 24 hours, both with chromatotron under the same conditions; another was solutions were mixed and then evaporated under reduced dealt with by way of utilizing dichloromethane with an ethyl pressure in vacuo. A crude extract was thus obtained, acetate relative: 1:0 and 0:1 v/v. The obtained compounds which was then subjected to a liquid–solid extraction using were characterized via several spectroscopic methods N-hexane (HEX), ethyl acetate (EA) and MeOH (the liquid (NMR, MS, IR, UV). The structures of the isolated alkaloids part). Both fractions were combined based on a thin-layer from the E. lepta are shown in Fig. 3 [29]: chromatography (TLC) profile, to give fraction A. Fractions CH3 A and B (MeOH) were then reacted with Dragendorff’s O reagent, which indicated the presence of alkaloids in fraction R1 A. This fraction (A) was then separated out by the silica gel CC method. Elution was next conducted with the use of O N O HEX, HEX/EA (gradient) and EA, yielding six sub-fractions. R2 H C CH Herein, maculine (12) was obtained. In further extractions, 2 3 isofagaridine, kokusaginine (13) and teclearverdoornine (14) No Compound R1 R2 were collected, and examined via NMR. The compounds 15 Leptanoine A – H – H isolated from aerial part of Z. buesgenii are shown in Fig. 2 16 Leptanoine B – OCH3 – H [28]: CH3 O CH3 R O 1 O O N O R2 O N O maculine (12) H3C CH3 H3C O H3C No Compound R1 R2 O 16 Leptanoine C – OCH – H O 3 17 Melineurine – H – H H3C N Fig. 3. The structures of the furoquinoline alkaloids isolated from O kokusaginine (13) the leafy material of Evodia lepta (Spreng.) Merr. H3C CH3 CH3 Cabral et al. [6] utilized stem material of Conchocarpus O fontanesianus (A. St.-Hill.) Kallunki&Pirani. in their work. O The extraction involved powdered material and ethanol, using an extractor under pressure at a temperature of 60°C. O N O The solution was then thickened in vacuum. Next, the OH teclearverdoornine (14) extract was dissolved in 0.1 M HCl, filtered and partitioned Figure 2. The furoquinoline alkaloids isolated from the aerial with hexane. The acid aqueous fraction was subsequently parts of Zanthoxylum buesgenii (Rutaceae) [28] treated with NH4OH and CHCl3. The alkaloid fraction was 34 Current Issues in Pharmacy and Medical Sciences Aldona Adamska-Szewczyk, Kazimierz Glowniak, Tomasz Baj then obtained, and TLC analysis was completed using substances on the larvae of Culex quinquefascintus [19]. The CHCl3:MeOH:NH4OH (90:7.5:2.5 v/v) as the eluent. This structure of tecleamaniensine A and tecleamaniensine B are alkaloid fraction was also analyzed via HPLC. In this work, presented in Fig. 4. in the stem material, the presence of dictamnine (1), skim- H C 3 CH3 mianine (2), γ-fagarine (3), 2-phenyl-1-methyl-quinoline CH3 and marmesine was confirmed [6]. O Tchinda et al. [31] investigated the bioactivity of dried H CO Zanthoxylum leprieurii (Guill. & Perr.) Engl. fruit. The 3 fruits, after blending, underwent extraction with ethyl H CO N O acetate. The concentrated extracts were subjected to column 3 tecleamaniensine A (18) chromatography (CC) with silica gel, and then eluted with CH3 CH3 EtOAc in petroleum ether. The fractions were subsequently H3C OH O collected and characterized by TLC. One of these was additionally chromatographed over CC, in petroleum ether - O using EtOAc at 80:20–75:35 v/v. The following compounds O H3CO N were isolated: 1-hydroxy-3,4-dimethoxy-N-methylacridone, tecleamaniensine B (19) tegerrardin A, arborinine, scoparone and xanthotoxoline. Figure 4. The structures of tecleamaniensine A and tecleamanien- The structural analysis of the compounds was completed by sine B isolated from Teclea amaniensis Engl. mass spectra and 1H and C13 NMR. The above-mentioned substances were assessed as coumarins and alkaloids, but Mwangi et al. [24] researched by chromatographic sepa- not furoquinolines [31]. ration, substances found in the leaves of Teclea trichocarpa Mora et al. [22] researched the chemical components of (Engl.) Engl. To accomplish this, the authors utilized a Zanthoxylum setulosum (P. Wilson). In their work, dried mixture of n-hexane, methanol and dichloromethane and aerial parts of the plant underwent extraction with methyl- extracted the plant material three times at room tempera- tert-butyl-ether (MTBE): methanol (MeOH) 9:1 v/v, for ture.