molecules Review Botanical Sources, Chemistry, Analysis, and Biological Activity of Furanocoumarins of Pharmaceutical Interest Renato Bruni 1 , Davide Barreca 2 , Michele Protti 3 , Virginia Brighenti 4, Laura Righetti 1 , Lisa Anceschi 4, Laura Mercolini 3 , Stefania Benvenuti 4, Giuseppe Gattuso 2 and Federica Pellati 4,* 1 Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; [email protected] (R.B.); [email protected] (L.R.) 2 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy; [email protected] (D.B.); [email protected] (G.G.) 3 Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; [email protected] (M.P.); [email protected] (L.M.) 4 Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy; [email protected] (V.B.); [email protected] (L.A.); [email protected] (S.B.) * Correspondence: [email protected]; Tel.: +39-059-205-8565 Received: 11 May 2019; Accepted: 6 June 2019; Published: 8 June 2019 Abstract: The aim of this work is to provide a critical review of plant furanocoumarins from different points of view, including their chemistry and biosynthetic pathways to their extraction, analysis, and synthesis, to the main biological activities found for these active compounds, in order to highlight their potential within pharmaceutical science. The limits and the possible improvements needed for research involving these molecules are also highlighted and discussed. Keywords: furanocoumarins; plants; botany; chemistry; extraction; analysis; biological activity 1. Biosynthesis of Furanocoumarins Furanocoumarins are tricyclic aromatic compounds composed of a furan ring fused to a α-benzopyrone (coumarin) system. Even though the furan moiety can be in either a 2,3- or 3,2-arrangement at the c, f, g, or h bonds of the coumarin, most naturally occurring derivatives belong to the psoralen (furo [3,2-g][1]benzopyran-7-one), allopsoralen (furo[2,3-f ][1]benzopyran-7-one), angelicin (furo[2,3-h][1]benzopyran-7-one), and furo[3,2-c]coumarin (furo[3,2-c][1]benzopyran-7-one) subclasses (Figure1). The whole class can be structurally divided into angular and linear furanocoumarins, with the latter being compounds with the furan ring attached at the 6,7 positions on the aromatic ring (e.g., angelicin), whereas in the former, the same ring is attached to the 7,8 positions (e.g., psoralen). In higher plants, the most abundant linear furanocoumarins are psoralen, xanthotoxin, bergapten, and isopimpinellin, while the most relevant angular furanocoumarins are angelicin, pimpinellin, sphondin, and isobergapten (Figure1). Molecules 2019, 24, 2163; doi:10.3390/molecules24112163 www.mdpi.com/journal/molecules Molecules 2019, 24, 2163 2 of 25 Molecules 2019, 24, x FOR PEER REVIEW 2 of 25 Figure 1. CoreCore structure structure of of the most common naturally occurring furocoumarin derivatives. Coumarins are lactones which can open on treatment with a base to to ciscis--oo-hydroxycinnamic-hydroxycinnamic acids and spontaneously cyclize again on acidification.acidification. Irradiation Irradiation of of the cis-cinnamate causes cis-trans isomerization and lactonisation. It It is is evident evident then then that that coumarins coumarins derive derive from from shikimic acid via cinnamic acids; organisms possessing an enzyme system capable of o-hydroxylating cinnamate are thus able to biosynthesize them. In detail, their biosynthesis proceeds proceeds from from umbe umbelliferonelliferone through through the the mevalonate mevalonate pathway pathway [1]. [1]. In plants, plants, umbelliferone umbelliferone (7-hydroxycoumarin, (7-hydroxycoumarin, Scheme Scheme 1) 1is) considered is considered as the as precursor the precursor of both of linear both andlinear angular and angular furanocoumarins. furanocoumarins. Umbelliferone Umbelliferone is a isphenylpropanoid a phenylpropanoid and and it itis is synthesized synthesized from Ll-phenylalanine, whichwhich in in turn turn is is produced produced via via the the shikimate shikimate pathway. pathway. The biosynthesisThe biosynthesis of both of linearboth linearand angular and angular coumarins coumarins proceeds proceeds via the prenylation via the prenylation either at the either 6-position at the for 6-position linear psoralens, for linear or psoralens,at the 8-position or at forthe angular8-position angelicins. for angular The enzymes,angelicins. 6 0The-prenyltranferase enzymes, 6′-prenyltranferase and 80-prenyltranferase, and 8′- prenyltranferase,using dimethylallyldiphosphate using dimethylallyldiphosp as the alkylatinghate agent, produceas the demethylsuberosinalkylating agent, and osthenol,produce demethylsuberosinrespectively [2]. Demethylsuberosin and osthenol, respectively is then converted [2]. Demethylsuberosin into (+)-marmesin is then by marmesinconverted synthase.into (+)- marmesinSubsequently, by marmesin psoralen synthase synthase. catalyzes Subsequently, the aromatization psoralen synthase of the dihydrofuran catalyzes the ring aromatization by the elimination of the dihydrofuranof an acetone moleculering by the (and elimination one hydrogen of an atom)acetone [3 ].molecule Psoralen (and 5-monooxygenase one hydrogen atom) and the [3]. analogous Psoralen 5-monooxygenase8-monooxygenase and oxidize the theanalogous respective 8-monooxygenase positions to produce oxidize bergaptol the respective and xanthotoxol, positions to which produce are bergaptolmethylated and each xanthotoxol, by their specific which Oare-methyltransferase methylated each [by4,5 ].their The specific formation O-methyltransferase of isopimpinellin, [4,5]. i.e., The5,8-dimethoxypsoralen, formation of isopimpinellin, has not been i.e., 5,8-dimeth elucidatedoxypsoralen, yet [6,7]. has not been elucidated yet [6,7]. As for thethe angularangular derivatives,derivatives, less less is is known known than than for for the the linear linear ones. ones. Osthenol Osthenol is convertedis converted by theby theenzyme, enzyme, columbianetin columbianetin synthase, synthase into, ( +into)-columbianetin, (+)-columbianetin, which iswhich in turn is transformedin turn transformed into angelicin into angelicinby an angelicin by an angelicin synthase [synthase8]. The enzymes [8]. The enzy for themes synthesis for the synthesis of sphondin of sphondin and pimpinellin and pimpinellin have not havebeen isolatednot been toisolated date. to date. 1.1. Chemical Chemical Diversity Diversity in Natural Furanocoumarins More than 50 natural furanocoumarins are known, and several screenings have revealed a consistent qualitative and quantitative quantitative heterogeneity heterogeneity at at both both intra-generic intra-generic and and intra-specific intra-specific level level [9]. [9]. As a result, a large variability in biological activities has been observed for plants containing furanocoumarins and and different different degrees degrees of oftoxicity toxicity and and drug drug interactions interactions may maybe encountered be encountered in those in usedthose as used foods as foods[10]. The [10]. literature The literature reports reports a wide a wide range range of concentrations, of concentrations, which which can canbe explained be explained by a combination of natural and genetic factors, influence of storage or processing, and by constraints at Molecules 2019, 24, 2163 3 of 25 by a combinationMolecules 2019, 24, of x FOR natural PEER REVIEW and genetic factors, influence of storage or processing, and by constraints3 of 25 at both sample treatment and analytical protocols [11]. Unfortunately, pharmacological studies have rarelyboth provided sample antreatment adequate and chemical analytical characterization protocols [11]. Unfortunately, of the plant material pharmacological and, at the studies same have time, the rarely provided an adequate chemical characterization of the plant material and, at the same time, evaluation of the dietary intake for furanocoumarins is considered extremely difficult [12]. On this the evaluation of the dietary intake for furanocoumarins is considered extremely difficult [12]. On regard,this data regard, on averagedata on average human human consumption consumption from from food food plants plants are deemedare deemed scarcely scarcely reliable reliable and and actual exposureactual could exposure exceed could published exceed published estimates estimates by an orderby an oforder magnitude of magnitude [13]. [13]. SchemeScheme 1. Biosynthetic 1. Biosynthetic pathways pathways to to linear linear and angular angular furanocoumarins furanocoumarins starting starting from from umbelliferone. umbelliferone. This scenario can be explained by the peculiar nature of these substances, whose histological accumulation and distribution may differ from those usually found for other secondary metabolites. Molecules 2019, 24, 2163 4 of 25 Furanocoumarins represent in fact a striking example of evolution-driven phytochemical diversity, whose peculiarity have relapses on the definition of the optimal protocols for the analytical determination of their content in plants and food. From a chemotaxonomical standpoint, furanocoumarins have been isolated from few genera within a limited group of plant families, including Apiaceae, Fabaceae, Moraceae, and Rutaceae and, to a minor degree, Amaranthaceae,