antibiotics Review Isolation and Biological Properties of the Natural Flavonoids Pectolinarin and Pectolinarigenin—A Review Thamere Cheriet 1,2,*, Balkeis Ben-Bachir 2, Oumelkhir Thamri 2, Ramdane Seghiri 1 and Ines Mancini 3,* 1 Unité de Valorisation des Ressources Naturelles, Molécules Bioactives et Analyse Physicochimiques et Biologiques (VARENBIOMOL), Université des Frères Mentouri, 25000 Constantine, Algeria; [email protected] 2 Département de Chimie, Faculté des Sciences, Université Mohamed Boudiaf-M’sila, 28000 M’sila, Algeria; [email protected] (B.B.-B.); [email protected] (O.T.) 3 Laboratorio di Chimica Bioorganica, Dipartimento di Fisica, Universita’ di Trento, I-38123 Povo-Trento, Italy * Correspondence: [email protected] (T.C.); [email protected] (I.M.); Tel.: +213-31-81-11-03 (T.C.); +39-0461-281548 (I.M.); Fax: +213-31-81-11-03 (T.C.) Received: 16 June 2020; Accepted: 5 July 2020; Published: 16 July 2020 Abstract: Flavonoids are metabolites widely distributed in plants and commonly present in foods, such as fruits and vegetables. Pectolinarin, which belongs to the flavone subclass, has attracted considerable attention due to its presence in many medicinal plants. It has turned out to be a good biological agent especially due to its antioxidant, anti-inflammatory, antidiabetic, and antitumor activities, evaluated both in vitro and in vivo. Its aglycone, the metabolite pectolinarigenin, is also known for a series of biological properties including anti-inflammatory and antidiabetic effects. In the first overview on the two metabolites here presented, their collection, isolation and the results of their biological evaluation are reported. Keywords: biological activities; antitumor; antidiabetic; anti-inflammatory 1. Introduction Nature is recognized as a source of molecules with relevant potential pharmaceutical applications, also in the 21st century. Among the various phytochemicals, flavonoids have attracted and are still attracting most of the attention due to their notable biological benefits. Based on several evidences, flavonoids have been associated with the role of preventing and managing current diseases such as cancers, diabetes, and cardiovascular disorders. More than 13,000 flavonoids were isolated and identified from plants, some of which like quercetin, kampferol and scutellarin showed potent pharmacological effects [1] and, therefore, are promising for new drugs. The glycosylated flavone pectolinarin was first isolated from Linaria vulgaris [2], a known medicinal Chinese herb used for the internal treatement of digestion problems and urinary disorders, in the external treatment of haemorrhoids, venous skin ulcer, as well as for the washing of festering wounds and skin rashes. It has also displayed anti-inflammatory effect [3] and has been used to treat coughs and asthma [4]. The structure of pectolinarin was determined to be a rutinoside conjugate of pectolinarigenin (=5,7-dihydroxy-4,6-dimethoxyflavone, C17H14O6) at the 7-O position (pectolinarigenin-7-O-rutinoside, C29H34O15) (Figure1). Antibiotics 2020, 9, 417; doi:10.3390/antibiotics9070417 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, 417 2 of 32 Antibiotics 2020, 9, x FOR PEER REVIEW 2 of 31 Figure 1. Molecular structures of pectolinarinpectolinarin and pectolinarigenin. Later, pectolinarinpectolinarin andand itsits aglycone pectolinarigeninpectolinarigenin were identifiedidentified asas the major constituents in many medicinal herbs from didifferenfferentt generagenera aroundaround thethe world.world. Several studies reported so far prove that the presence ofof these two flavonesflavones has an importantimportant role in aaffectingffecting the biological properties of the followingfollowing herbs:herbs: i) the Korean herb Cirsium setidens (Dunn) Nakai employed for the treatment of hemostasis, hematemesis, hematuria and hypertensionhypertension [[5];5]; ii) the Chinese herb Cirsium chanroenicum used for detoxification,detoxification, to treat fever and to enhance blood circulation [6]; [6]; iii) Cirsium japonicum DC. employed as an anti-hemorrhagic and uretic agent, as well as prescribed to treat liver and uterineuterine tumours, and leukemialeukemia [[7];7]; iv)iv) KickxiaKickxia ramosissimaramosissima (Wall.)(Wall.) Janch., used in PakistanPakistan folkfolk medicinemedicine asas diuretic and against kidney stones [[8],8], fever and rheumatismrheumatism [[9],9], andand duringduring managementmanagement of snakesnake and scorpionscorpion bitesbites [[10];10]; v)v)Lantana Lantana camara camaraL., L., used used for for the the treatment treatment of of various various human human ailments, ailments, such such as ulcers,as ulcers, malaria, malaria, influenza, influenza, tumors, tumors, swellings, swellings, bilious bilious fever, eczema fever, eruptions,eczema eruptions, stomach ache,stomach toothache, ache, andtoothache, as antiseptic and as for antiseptic wounds for [11 wounds]; and vi) [11];Picnomon and vi) acama Picnomon(L.) Cass., acama used (L.) inCass., Greek used folk in medicine Greek folk as hemostaticmedicine as and hemostatic spasmolytic and agentspasmolytic [12]. agent [12]. Due to the structural similarity of pectolinarigenin to known potent flavonoidsflavonoids such as acacetin (5,7-dihydroxy-4(5,7-dihydroxy-4′0-methoxyflavone,-methoxyflavone, CC1616HH1212OO5),5), hispidulin hispidulin (4(40′,5,7-trihydroxy-6-methoxyflavone,,5,7-trihydroxy-6-methoxyflavone, C16HH1212OO6)6 )and and scutellarein scutellarein (5,6,7,4 (5,6,7,4′0-tetrahydroxyflavone,-tetrahydroxyflavone, C15HH1010OO6)6 )and and based based on on the the numerous numerous data reported forfor both both pectolinarin pectolinarin and pectolinarigenin,and pectolinarigenin, the aim the of thisaim work of isthis to providework is a comprehensiveto provide a overviewcomprehensive focusing overview on their focusing isolation, pharmacologicalon their isolation, aspects pharmacological and therapeutic aspects potential. and therapeutic potential. 2. Isolation of Pectolinarin and Pectolinarigenin 2. IsolationOver the of lastPectolinarin 113 years and from Pectolinarigenin its first report [2 ], pectolinarin was isolated in most cases from the aerialOver parts the of 87last plants 113 years belonging from toits 29 first diff reporterents genera[2], pectolinarin distributing was widely isolated around in most the world.cases from Most the of theseaerial plantsparts of are 87 used plants in folkbelonging medicine to 29 in differents different parts genera of thedistributing world. Table widely1 gathers around the the 87 world. plants fromMost whichof these pectolinarin plants are used was isolated.in folk medicine in different parts of the world. Table 1 gathers the 87 plants from which pectolinarin was isolated. Table 1. Isolation of pectolinarin from the indicated plants, classified according to family, genus and species, and place of collection. Table 1. Isolation of pectolinarin from the indicated plants, classified according to family, genus and Genusspecies, and place of collection. Species Collection Place Reference GenusFamily: AdoxaceaeSpecies Collection Place Reference Family: Adoxaceae V. cotinifolium Kashmir/India [13] Viburnum V. cotinifoliumV. mullaha Kashmir/IndiaIndian Himalayan region [14[13]] Viburnum Family: AsteraceaeV. mullaha Indian Himalayan region [14] Family: Asteraceae C. subcoriaceum Pahuatlan/Mexico [15] Daejeon/S. Korea, Oberndorf/Austria, C. C. japonicumPahuatlan/Mexico [7,16[15]–20 ] Chengdu/China, Henan/China subcoriaceum Daejeon/S. Korea, Oberndorf/Austria, Chengdu/China, [7,16–20] Oberndorf/Austria C. japonicum Henan/China Cirsium Bialystok/Poland Oberndorf/AustriaDaejeon /S. Korea C. setosumBialystok/PolandDaejeon /S. Korea [18 ] Cirsium Daejeon/S. KoreaDaejeon, Wonju, Pyongchang-gun, [18] C. setosum C. rivulareDaejeon/S. KoreaGangwondo, Jeongseon-gun, Yanggu/S. [21[21]] Korea C. rivulare Daejeon, Wonju, Pyongchang-gun, Gangwondo, [19] C. lineare Jeongseon-gun, Yanggu/S. Korea [19,22] C. nipponicum Daejeon/S. Korea [19,23–26] Antibiotics 2020, 9, 417 3 of 32 Table 1. Cont. Genus Species Collection Place Reference C. lineare Daejeon/S. Korea [19] C. nipponicum Daejeon, Sancheong/S. Korea [19,22] C. setidens Jeongseon-gun, Jeju Island/S. Korea [19,23–26] Laramie/USA Laramie/USA, Vitebsk/Belarus Nemuro, Hatimandake, Memanbetsu, C. pendulum [19] Onsen Kyushu, Hokkaido/Japan C. chanroenicum [19,26,27] C. rhinoceros [28,29] C. coloradense Wyoming/USA, Japan [30] Mount Akaishi, Mount Senmai, Shizuoka, C. arisanense Takanomori, Nekura Valley/Japan, Vitebsk/Belarus, C. tioganum Mount Shirouma/Japan C. oleraceum la Dotze/Switzerland [30–32] Hsien/Taiwan Nemuro, Mount Shirouma /Japan, Mount C. microspicatum [16] Ali, Chiayi Hsien/Taiwan C. babanum Ku Kuan, Taichung Haien/Taiwan Mount Shirouma, Mount Hakusan ad C. kagamontanum pedem/Japan C. inundatum Vancouver/Canada Cirsium C. dipsacolepis Seongnam/Korea C. brevicaule C. yezoense C. kamtschaticum C. pectinellum C. bitchuense [33,34] C. senjonse [17,31,35–37] C. spicatum C. yezonese C. vallis-demonii C. gratiosum C. indundatum C. otayae [35] C. purpuratum C. spinosissimum [38] C. spinosum [34] C. ferum [39] C. kawakamii [16,40,41] C. wallichii [41] C. yoshizawae [35] C. matsumurae [34,40] C. brevistylum [42] C. chlorolepis [43] Duranta D. plumieri Rajshahi/Bangladesh [44] Hemistepta H. lyrata Kangwon/S. Korea [45] Picnomon P. acarna Mount Hortiatis/Greece [46] Family: Bignoniaceae Distictella D. elongata Minas Gerais State/Brazil [47] Markhamia M. lutea Benguluru/India [48] Family: Buddlejaceae