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Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

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Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids International Journal of Molecular Sciences Review Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids Francesca Ghirga 1, Alessandra Bonamore 2,*, Lorenzo Calisti 2, Ilaria D’Acquarica 3,* ID , Mattia Mori 1, Bruno Botta 3 ID , Alberto Boffi 2 and Alberto Macone 2,* ID 1 Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; [email protected] (F.G.); [email protected] (M.M.) 2 Deaprtment of Biochemical Sciences “A.Rossi Fanelli”, Sapienza University of Rome, Pizzale Aldo Moro 5, 00185 Rome, Italy; [email protected] (L.C.); alberto.boffi@uniroma1.it (A.B.) 3 Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Pizzale Aldo Moro 5, 00185 Rome, Italy; [email protected] * Correspondence: [email protected] (A.B.); [email protected] (I.D.); [email protected] (A.M.); Tel.: +39-06-49910813 (A.M.) Received: 6 November 2017; Accepted: 16 November 2017; Published: 20 November 2017 Abstract: Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes. Keywords: alkaloids; benzylisoquinoline alkaloids; green synthesis; recombinant enzymes; microbial factories 1. Introduction Benzylisoquinoline alkaloids (BIAs) are a nitrogen-containing group of plant secondary metabolites with a centenary history of investigation [1]. The interest in the wide variety of BIA structures is paramount, due to their well-established and long-standing pharmacological profiles [2]. The most covered therapeutic areas by BIAs are analgesics [3,4], antimicrobial [5], antimalarial [6,7], anti-HIV [7–9], and anticancer agents [10–12], whereas new areas are being explored more recently for BIAs, such as their employment as cholesterol-lowering and protecting agents against the atherosclerotic disease [13–16] and as signaling suppressors in colon cancer cells [17]. In 2010, with the aim of providing comprehensive information about both the source and the medicinal properties of BIAs, there was created an ad hoc database of benzylisoquinolines compounds, called BIAdb, helpful for all those who are working in the field of drug discovery, to explore the pharmacological potential of BIAs [18]. One of the most important features of BIAdb is that it provides information about 627 plant species as a source of benzylisoquinoline and 114 biological activities shown by these compounds. A lot of tools have been integrated in the database, which help users in discovering the full potential of the program itself. The general benzylisoquinoline skeleton (Figure1) can be mostly synthesized (with few exceptions) by a cyclization reaction, namely, the Pictet-Spengler (P-S) reaction, which has been the subject of a huge number of review articles [19–22] and in 2011 has entered its second century Int. J. Mol. Sci. 2017, 18, 2464; doi:10.3390/ijms18112464 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 2464 2 of 19 Int. J. Mol. Sci. 2017, 18, 2464 2 of 18 of lifeInt. [23 J. Mol.,24 ].Sci. Nowadays, 2017, 18, 2464 the P-S reaction is still one of the most employed synthetic tools2 of not 18 only [23,24]. Nowadays, the P-S reaction is still one of the most employed synthetic tools not only to yield Int. J. Mol. Sci. 2017, 18, 2464 β 2 of 18 to yield[23,24].tetrahydroisoquinolines tetrahydroisoquinolines Nowadays, the P-S (THIQs) reaction (THIQs) and is still tetrahydro- one and of tetrahydro- theβ most-carbolines employed-carbolines (THBCs), synthetic (THBCs),but tools also not to but onlybuild also to novelyield to build novel scaffolds for structure-activity relationship studies and/or for combinatorial libraries for drug tetrahydroisoquinolinesscaffolds[23,24]. Nowadays, for structure-activity the P-S (THIQs) reaction relationship and is stilltetrahydro- one stud of theiesβ-carbolines most and/or employed for (THBCs), combinatorial synthetic but toolsalso libraries notto buildonly for to novel drugyield discoveryscaffoldsdiscoverytetrahydroisoquinolines programs. forprograms. structure-activity (THIQs) relationship and tetrahydro- studiesβ-carbolines and/or for (THBCs),combinatorial but also libraries to build for noveldrug discoveryscaffolds programs.for structure-activity relationship studies and/or for combinatorial libraries for drug R discovery programs. R N RR R H N RR R H N RR R H RR R FigureFigure 1. The1. The benzylisoquinoline benzylisoquinoline skeleton (R (R = =H, H, OH, OH, OMe). OMe). Figure 1. The benzylisoquinolineR skeleton (R = H, OH, OMe). The P-S reaction is essentially an electrophilic aromatic substitution and can be described as a Figure 1. The benzylisoquinoline skeleton (R = H, OH, OMe). ThemodificationThe P-S P-S reaction reactionof the isMannich is essentially essentially reaction. anan electrophilicelectrophilicThe name comes aromatic aromatic from substitution the substitution chemists and Pictet andcan and be can describedSpengler, be described whoas a as a modificationmodificationsynthesizedThe P-Sof 1-methyl-1,2,3,4-tetrahydroisoquinoline ofreaction the the MannichMannich is essentially reac reaction.tion. an The electrophilic The name name comes aromatic (Scheme comes from thefromsubstitution1) inchemists 1911, the chemistsby andPictet cyclocondensation can and Pictetbe Spengler, described and ofwho Spengler, as β a- who synthesizedphenethylaminemodification 1-methyl-1,2,3,4-tetrahydroisoquinoline 1-methyl-1,2,3,4-tetrahydroisoquinolineof thewith Mannich acetaldehyde reaction. dimethyl The name acetal comes (Schemecatalyzed from (Scheme 1)the byin chemists 11911,HCl) in 1911,[25].by Pictet cyclocondensation With by and cyclocondensation the Spengler, exception of who βof- of β-phenethylaminephenethylamineformaldehyde,synthesized 1-methyl-1,2,3,4-tetrahydroisoquinoline any withwith aldehyde acetaldehydeacetaldehyde which isdimethyl dimethyl submitted acetal acetal to the catalyzed(Scheme catalyzedP-S reaction 1) by in byHCl1911, creates HCl [25]. by [acyclocondensation 25 Withnew]. With chiralitythe exception the centre exception of ofatβ- of formaldehyde,formaldehyde,thephenethylamine C-1 carbon any anyatom aldehyde with aldehyde of acetaldehydethe THIQ which which sk is eleton;is dimethyl submitted submitted this acetalis to tothe the the reasoncatalyzed P-S P-S reaction why reaction by the HClcreates stereoselectivity creates [25]. a newWith a new chirality the of chirality exceptionthe centre reaction centre atof at the C-1theinformaldehyde, the carbonC-1 synthesis carbon atom atom anyof of isoquinoline thealdehyde of the THIQ THIQ which skeleton; alkaloids skeleton; is submitted thishas this b is eenis the theto an reason thereason ancient P-S whyreactionwhy competition the createsstereoselectivity stereoselectivity for a organicnew chirality chemists.of of the the reactioncentre reaction at in in the synthesis of isoquinoline alkaloids has been an ancient competition for organic chemists. the synthesisthe C-1 carbon of isoquinoline atom of the alkaloids THIQ skeleton; has been this anis the ancient reason competition why the stereoselectivity for organic chemists.of the reaction in the synthesis of isoquinoline alkaloids has been an ancient competition for organic chemists. Scheme 1. First appearance of the Pictet-Spengler (P-S) reaction. The asterisk denotes the chirality SchemeSchemecentre 1. atFirst 1. C-1. First appearance appearance of of the the Pictet-Spengler Pictet-Spengler (P-S (P-S)) reaction. reaction. The The asterisk asterisk denotes denotes the chirality the chirality centre at C-1. centreScheme at C-1.1. First appearance of the Pictet-Spengler (P-S) reaction. The asterisk denotes the chirality Despite the huge structural diversity, BIAs have the same biosynthetic precursor, namely (S)- centre at C-1. DespitenorcoclaurineDespite the the huge(Schemehuge structural structural 2), which diversity, diversity, is BIAsformed ha BIAsve bythe havesamecondensation biosynthetic the same of precursor, biosyntheticdopamine namely and precursor, (S4-)- norcoclaurinehydroxyphenylacetaldehyde (Scheme 2), (4-HPAA),which is withformed an ex cellentby condensation stereoselectivity of [26,27].dopamine The andenzyme 4- namely (DespiteS)-norcoclaurine the huge structural (Scheme diversity,2), which BIAs is ha formedve the same by biosynthetic condensation precursor, of dopamine namely (S)- and hydroxyphenylacetaldehydeinvolved in the biosynthesis is(4-HPAA), the norcoclaurine with an synthase excellent (NCS; stereoselectivity EC 4.2.1.78), which[26,27]. can The be enzymedefined 4-hydroxyphenylacetaldehydenorcoclaurine (Scheme 2), (4-HPAA),which is withformed an excellentby condensation stereoselectivity of dopamine [26,27]. Theand enzyme4- involvedas a “Pictet-Spenglerase”. in the biosynthesis
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