Review Received: 19 September 2014

Revised: 16 October 2014

Accepted: 20 October 2014

Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI 10.1002/psc.2719

Multifunctional adamantane derivatives as new scaffolds for the multipresentation of bioactive peptides‡ Maxime Grillaud and Alberto Bianco* The remarkable structural and chemical properties of adamantane afford attractive opportunities to design various adamantanebased scaffolds for biomedical applications. A wide range of mono-functionalized adamantane compounds have already been investigated and reviewed, mostly as anti-viral agents. The four bridgehead positions of adamantane provide many possibilities to design poly-functional derivatives, and the recent conception of adamantane building blocks with multiple substituents has shown promising applications in several domains. In this review, we provide a detailed description of the different ways to synthesize multifunctional derivatives starting from adamantane molecule as the main core. We will then describe the interesting biological activity of the diverse multivalent scaffolds, focusing in particular on peptide-based systems. The results reported here will certainly encourage the development of novel adamantane-based structures for biological purposes. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. Keywords: adamantane; scaffold; multi-functionalization; peptide; multivalency

Introduction Adamantane molecule, corresponding to C10H16 formula, is a rigid structure consisting of four cyclohexane rings fused in chair conformation. The spatial arrangement of the carbon atoms of this polycyclic cage is similar to that in the unit cell of diamond crystal lattice with an almost identical carbon–carbon bond length corresponding to 1.54 Å [1,2]. The molecule presents a tetrahedral symmetry and its 10 carbons and 16 hydrogens can be distinguished into only two equivalent sites, the bridge and bridgehead positions (Figure 1). Adamantane can be isolated from different natural sources such as crude oil, natural gas, and sediments. Indeed, its first identification was obtained from a sample of petroleum near Hodonin in Czechoslovakia in 1933 by Landa and Machacek [3,4]. It is the lowest diamondoid form followed by diamantane, which was also discovered in the same crude oil in 1966 [5,6]. Today, the molecule is generated in large quantities by thermal cracking of high molecular mass fractions from crude oils. Adamantane can also be synthesized at the laboratory scale. The first syntheses were performed in 1941 by Prelog and Steinwerth and later by Stetter et al. [7–9]. The two methods gave a production with very low yields in several steps. A more convenient method was found by Schleyer in 1957 starting from dicyclopentadiene hydrogenation followed by tetrahydrodicyclopentadiene rearrangement into adamantane providing an affordable source [10,11]. Nowadays, the chemical compound costs less than $1/gram. Adamantane is highly reactive compared with other hydrocarbons, and many derivatives designed from adamantyl motif were developed for different applications, especially in medicinal chemistry. Indeed, the discovery of the potent inhibitory properties of 1-aminoadamantane, or amantadine, against a range of viruses, including Influenza A [12] and Rubella [13] in the 1960s gave birth to a novel important research field. The well-defined 3D conformation, the hydrophobicity, and the lipophilicity provide to adamantane-based compounds favorable properties for their transport through biological membranes. Many

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investigations using a large number of derivatives were performed for biomedical applications, mostly as anti-viral agents [14–19]. Today, seven drugs incorporate the adamantane motif, and various compounds are currently in development as new potential pharmaceutics. The medicinal chemistry of adamantane derivatives has been newly reviewed [20,21]. In particular, Schreiner et al. reported an exhaustive description of the therapeutic applications for a wide range of diseases using drug candidates incorporating an adamantane moiety. Almost all these compounds are mono-functionalized in one position of the adamantane scaffold to generate highly specific inhibitors for various targeted receptors. Different positions of the backbone structure can be also modified to afford poly-functional adamantane molecules with interesting properties. Chemists mainly used the bridgehead positions for functionalization due to an easy selective activation of C–H bond for a direct nucleophilic substitution or for radical reactions [22–25]. Furthermore, the introduction of substituents in these four sites offers a molecular toolbox for the design of tetravalent scaffolds [26]. Various multi-functional adamantane compounds are used in several application domains such as catalysis [27–29], supramolecular chemistry [30–33], surface functionalization [34–36], biocompatible surface tailoring [37,38], materials science [39–41], and for the development of multivalent systems for biological purposes, which is the topic of this review. We will first focus on the synthesis of adamantane scaffolds with multiple functions in the bridgehead positions and * Correspondence to: Alberto Bianco, CNRS, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique, Strasbourg, France. E-mail: [email protected]

th

Special issue of contributions presented at the 14 Naples Workshop on Bioactive Peptides “The renaissance era of peptides in drug discovery”, June 12-14, 2014, Naples. CNRS, Institut de Biologie Moléculaire et, Cellulaire, Immunopathologie et Chimie Thérapeutique, Strasbourg, France

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GRILLAUD AND BIANCO

Biography Dr. Maxime Grillaud received his Master’s degree in Nanosciences and Chemistry of Life from the University of Bordeaux (France) in 2011 including an internship on functionalization of gold nanoparticles with Pr. Didier Astruc. After his graduation, he completed his PhD in Chemistry at the University of Strasbourg under the guidance of Dr. Alberto Bianco. His work focused on the synthesis and the characterization of adamantane-based dendrons for biological purposes. He is currently a postdoctoral research associate in the group of Dr. Alberto Bianco at the Institut de Biologie Moléculaire et Cellulaire (Strasbourg, France) working on the functionalization of graphene oxide for biological applications.

been extensively investigated, especially in ionic reactions where carbocations are formed as intermediates [42]. In terms of selectivity, its functionalization is very easy because of the presence of only two different reactive sites: the six secondary and the four tertiary carbon atoms corresponding to the bridge and the bridgehead positions, respectively (Figure 1). The most common first step to functionalize adamantane backbone is the halogenation in the bridgehead positions using selective C–H activation of the tertiary carbon atoms, which display the most stable carbocations as intermediates [22–25,42]. Other various types of synthesis have been also widely reviewed [43–45], in particular adamantane rearrangements [46], the formation of unsaturated derivatives [47], or the introduction of heterocylic substituents [48]. More recently, diverse poly-functionalizations of adamantane with different residues in the bridgehead positions have been reported [49], especially for the preparation of molecular tripods for surface tailoring including self-assembling monolayers, TiO2 semiconductor surfaces, and atomic force microscopy gold tip modification. Multi-functionalization of the Bridgehead Positions Starting from Adamantane Core

Biography Dr. Alberto Bianco received his ‘Laurea’ (Master) degree in Chemistry in 1992 and his PhD in 1995 from the University of Padova (Italy). As a visiting scientist, he worked at the University of Lausanne during 1992, at the University of Tübingen in 1996–1997 (as an Alexander von Humboldt fellow), and at the University of Padova in 1997–1998. He is currently a research director at the CNRS in Strasbourg (France). His research interests focus on the design and functionalization of carbon-based nanomaterials (carbon nanotubes, fullerenes, graphene, and adamantane) and their use for therapeutic, diagnostic, and imaging applications; the development of functionalized carbon nanotubes and graphene in nanomedicine; and the study of their impact on health and environment. He is an author and a co-author of over 190 papers. He is a member of the American Chemical Society, the French Group of Peptides and Proteins, and the European Peptide Society. He is also in the Advisory Board of Nanomedicine (Lond.) and the Journal of Peptide Science. He is an editor of Nanotechnology Reviews and Carbon. then on the different biological applications using multi-functional adamantane derivatives. In particular, we will describe the use of adamantane for the multipresentation of bioactive peptides. Synthesis of Multi-functional Adamantane Scaffolds Although hydrocarbons containing only C–H bonds are usually chemically inert, the derivatization of the adamantane structure has

Figure 1. The two equivalent positions on adamantane structure.

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Although the formation of mono-functionalized adamantane compounds is simple, the synthesis of derivatives with multiple substituents necessitates more drastic reaction conditions. The substitutions in the bridgehead positions become more difficult with the number of attached electron-withdrawing residues due to statistical and/or electronic effects. The reactivity at each bridgehead position is therefore strongly dependent on the substituents at the other positions. The first step in the construction of multi-functional compounds is generally the bromination of adamantane, which permits the introduction of one to four bromines in the bridgehead positions using suitable catalysts and conditions [2,43–45,50,51]. Each bromine becomes more difficult to insert than the last, and generally, harsh conditions are required to produce tribromo- and tetrabromoadamantane. This allows to choose a proper protocol for the selective synthesis of each bromine derivative [26,52]. Another method for the selective C–H activation to introduce bromines into the bridgehead positions of adamantane structure is the phase-transfer catalysis (PTC) in mixed aqueous/organic solvents [22–25,53]. This procedure also permits the insertion of bromine into the remaining available tertiary carbon atoms from methylfunctionalized adamantane compounds. The multiple bridgehead fluorination of adamantane is also realizable via the incorporation of each fluorine step by step. The commercially available bi-functional 3-hydroxyadamantane carboxylic acid is synthesized from adamantane [54], and its conversion to 3-fluoroadamantane-1-carboxylic acid is easily obtained [55,56]. The latter can be directly transformed into 3-fluoroadamantane-1-amine, and a practical route permits the subsequent synthesis of the corresponding multi-fluorinated 3,5,7-tri-fluoroadamantane-1-carboxylic acid and 3,5,7-trifluoroadamantane-1-amine [57]. This process is carried out via the introduction of a hydroxyl group in one bridgehead position followed by its substitution with fluorine and protection/deprotection of the carboxylic acid or the amine function. The intermediates with two fluorines can also be isolated. Two methods for a direct multi-fluorination of adamantane are also reported. The first one consists of reacting adamantane with iodine pentafluorine reagent [58]. This preparation allows the synthesis of monofluorinated compound and it is possible to move toward the reaction for the formation of 1,3-difluoroadamantane by increasing the temperature in the presence of an excess amount of iodine pentafluorine reaching a yield of 75%. The second procedure is an electrochemical fluorination using Et3N–5HF as both an

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MULTIFUNCTIONAL ADAMANTANE electrolyte and a fluorine source [59]. The control of the oxidation potential affords selective synthesis of monofluoroadamantane, difluoroadamantane, trifluoroadamantane, and tetrafluoroadamantane. These two processes also permit the insertion of the halogen on the remaining non-functionalized bridgehead positions of mono-functional or bi-functional adamantane derivatives. Futhermore, the selective incorporation of diverse moieties including methyl, phenacyl, aryl, cyclohexyl, alkoxy, or azido groups by substitution of the fluorine is performed with high yields [60]. Following the PTC protocol, the functionalization of adamantane with different halogens (fluorine, chlorine, bromine, and fluorine) is operated step by step to give bihalogenated, trihalogenated, or tetrahalogenated derivatives [61]. Different combinations of desired halogen insertions are achievable until the formation of the fully substituted 1-bromo-3-chloro-5-fluoro-7-iodoadamantane. The halogen exchange is also possible by choosing the appropriate conditions [62]. In general, the solvents used are CH3I or CH2I2 for iodine transfer, CH2Br2 or CHBr3 for bromine transfer, and CHCl3 or CC14 for chlorine transfer. The synthesis of tetra-halogenated compounds with the same halogen at each bridgehead position is performed in one single step (Table 1: compounds 1, 2, and 3) [63–65]. However, these products are quite difficult to functionalize to obtain more complex structures due to low solubility and reactivity. Other tetra-functionalized adamantanes, such as 1,3,5,7-tetraacetamidoadamantane (Table 1: compound 4), 1,3,5,7-tetraaminoadamantane tetrahydrochloride (Table 1: compound 5), and 1,3,5,7-tetranitroadamantane (Table 1: compound 6), can be prepared very easily [64,65]. A key compound for numerous applications is adamantane bearing four carboxylic acids (Table 1: compound 7) [66]. Its water solubility and high reactivity for the construction of diverse tetravalent adamantane scaffolds make it very attractive, but its first synthesis afforded tiny quantities [7]. Alternative methods to synthesize it from adamantane were developed through photochemical reactions via the formation of the tetramethyl ester intermediate (Table 1: compound 8), which can be easily hydrolyzed. The first one consists in the irradiation of a solution of the commercially available adamantane monocarboxylic or dicarboxylic acids with oxalyl chloride under UV light [67]. Subsequent esterification of the reaction mixture with methanol gives 8 with a yield up to 40%. The second possibility to obtain 8 under irradiation is the radical nucleophilic substitution reaction of 1 with cyanide to provide 1,3,5,7-tetracyanoadamantane (Table 1: compound 9) [40,63]. Compound 9 can then afford both 8 by solvolysis with methanolic anhydrous HCl and tetrakis(aminomethyl)adamantane tetrahydrochloride by reduction with borane reagents. The latter gives tetrakis (aminomethyl)adamantane (Table 1: compound 10) after treatment with concentrated NaOH. Adamantane can be directly converted and isolated into 1,3,5-tri(hydroxyl)adamantanol or into 1,3,5,7-tetra(hydroxyl)adamantanol (Table 1: compound 11) under mild conditions using an excess of methyl(trifluoromethyl) dioxirane in solution [68]. Derivative 11 is also produced from the tetrabromide 1 with high yield [32,41] and it is a key intermediate to obtain 8 in three steps without the need of a photochemical reactor [69]. Table 1 summarizes these tetra-functionalized adamantane derivatives with the same function in each bridgehead position with their corresponding yields and references. A recent approach for one-pot selective bi-functionalization of adamantane describes the introduction of various nucleophiles using CBr4 · 2AlBr3 as a superelectrophilic complex [70]. Although 1-bromoadamantane is also used as an interesting starting compound for the synthesis of diverse bifunctionalized derivatives [71], it is also useful for the formation of 1,3,5,7-tetraphenyladamantane

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(Table 1: compound 12) in one straightforward step via Friedel–Crafts reaction with benzene [72]. This preparation can provide 100 g of 12 with a yield up to 70%. The synthesis and isolation of 1-phenyladamantane, 1,3-diphenyladamantane, and 1,3,5-triphenyladamantane can be controlled by modifying the time of reaction and by successive filtrations using different solvents. Finally, the oxidative degradation of 12 with RuCl3 and an excess of periodic acid with subsequent esterification is another possible way to obtain 8 but with low yield and difficult purification steps [69]. Design of Various Multi-functionalized Adamantane Building Blocks As evident from the previous paragraph, adamantane is an interesting ‘starting block’ for the construction of complex architectures for many applications [27–41]. Its rigid structure is attractive for the development of multivalent scaffolds, which require a robust core. The design of adamantane building blocks is operated by playing with substituents in the bridgehead positions, so that diverse structures can be created according to the desired properties of adamantane scaffolds. To maintain the rigidity while allowing derivatization pathways, compound 12 can be considered the best initiator of various building blocks. Phenyl groups provide a lateral extension of the 3D adamantane core and they can be easily halogenated to afford a range of functionalization possibilities. Para-substitution at the extremity of the four aryl groups is performed through iodination [72–74] or bromination [72,73] with high yields. 1,3,5,7Tetrakis(4-iodophenyl)adamantane (13) can participate in numerous palladium catalyzed cross-coupling reactions including Suzuki– Miyaura [72,75,76], Sonogashira [29,36,73,75,77], Mizoroki–Heck [78], and multicomponent cascade reactions [27]. The preparation of ‘clickable’ building blocks from the tetraiodine derivative offers potential design of various adamantane scaffolds (Scheme 1). Direct substitution of the four iodine with azido groups allowed the formation of 1,3,5,7-tetrakis(4-azidophenyl)-adamantane (17) with very low yields [79]. A better way for tetra-azidation is performed via the formation of tetradiazonium salts generated from the corresponding tetraamine (16) [80]. The latter is produced from 12 in two easy steps (Scheme 1) [81,82]. Another possibility to create clickable scaffolds is the synthesis of the tetra-alkyne (14) through palladium-catalyzed coupling of the tetraiodine with 2-methyl-3-butyn-2-ol [72] or with trimethylsilylacetylene [73] followed by subsequent deprotection. Fourfold click reactions from these rigid building blocks give tetravalent molecules with an adamantane nucleus [79,80] including the formation of branched oligonucleotides [80,83] and/or glycoclusters [84]. The synthesis of 1,3,5,7-tetrakis(carboxylatophenyl)adamantane from 12 [72] is a laterally extended analog of the tetracarboxylic acid 7 soluble only in DMSO and hot acetic acid. Because C3-symmetry plays an important role in various areas including asymmetric catalysis [85,86], self-assembly [87,88], and molecular recognition [89,90], various tripodal scaffolds are designed. In biology, cyclohexanes, planar aromatics, cyclopeptides and many others molecules affording a threefold rotational geometry have been developed as efficient trivalent systems for high ligand/receptor interactions [91–93]. The need of a functionalizable rigid core with a tripodal arrangement renders therefore the trivalent adamantane-based building blocks attractive derivatives for diverse biological applications. Their construction with the shape of a tripod usually starts from adamantane bearing three functional groups. For example, 1,3,5tribromoadamantane (25) treated with vinyl bromide and AlCl3 followed by the subsequent elimination with tBuOK gives 1,3,5-tri(ethynyl) adamantane, which is easily purified [39,69,94,95]. The latter is the

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91% from 1 – overall 86%, two steps (63)

2

91% from 5 – overall 11%, five steps (64) 45% from 5 – overall 10%, five steps (65)

12

11

85% from 4 – overall 22%, four steps (65)

5

6

10

60% from 2 – overall 26%, three steps (65) 48% from 2 – overall 16%, three steps (64)

4

76% from 4 – overall 12%, four steps (64)

9

98% – one step (63)

3

81% from 1 – overall 44%, two steps (65) 64% from 1 – overall 33%, two steps (64)

7

Structures and derivative names

94% – one step (63) 58% – one step (65) 52% – one step (64)

Yields – number of steps (References)

1

Structures and derivative names

70% from 1–bromoadamantane overall 66%, 2 steps (72)

70% – one step (68) 78% from 1 – overall 49%, two steps (41) 75% from 1 – overall 48%, two steps (32)

84% from 13 – overall 58, four steps (63)

73% from 1 – overall 69%, two steps (63)

40% – overall 32%, two steps (67) (from 1,3-adamantanedicarboxylic acid (70)) 72% from 13 – overall 49%, three steps (63) 29% from 11 – overall 20%, four steps (69) 35% from 12 – overall 14%, four steps (69)

Quantitative from 12 – overall 49%, four steps (63)

Yields – number of steps (References)

Table 1. Tetra-functionalized derivatives with the same substituent in each bridgehead position. Overall yields and number of steps correspond to the synthesis starting from adamantane

GRILLAUD AND BIANCO

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MULTIFUNCTIONAL ADAMANTANE

Scheme 1. Synthesis of rigid tetrahedral ‘clickable’ adamantane-based building blocks [72,73,80–82].

precursor for the preparation of a number of tripodal building blocks such as the synthesis of tricarboxylic acids derivatives [69,95], the creation of big complex architectures [28,39,96], and for the direct attachment of oligonucleotides strands [97]. The tripod 1,3,5-adamantane tricarboxylic acid (20) is easily obtained from both oxidative reactions of 1,3,5-tri(phenyl)adamantane

(18) or of 1,3,5-tri(hydroxyl)adamantane (19) and it can provide a series of other rigid tri-functional building blocks such as 1,3,5tris(hydroxymethyl)adamantane (22), 1,3,5-triaminoadamantane (23), and 1,3,5-tris(1,2,4-triazol-4-yl)adamantane (24) (Scheme 2) [40,69]. In order to gain in flexibility, it is also possible to introduce a spacer between the adamantane core and the functional groups. For instance,

Scheme 2. Synthesis of diverse tripodal rigid [40,69] and semi-rigid [69] adamantane-based building blocks.

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GRILLAUD AND BIANCO 1,3,5-tribromoadamantane (25) is transformed into a semi-rigid tricyano derivative (26) via radical chemistry, and the latter affords a succession of flexible building blocks (compounds 27, 28, 29, and 30) (Scheme 2) [69]. These tripodal scaffolds consist of three functionalized bridgehead positions, whereas the fourth reactive site is still available for derivatization. Incorporation of an orthogonal function in the fourth remaining position provides ‘(3 + 1) scaffolds’, which present both a C3-symmetry and an orthogonal functionality pointing into the opposite direction [26]. These structures lead to the formation of building blocks, which combine trivalency and the opportunity for further conjugation with ligands such as dyes, targeting agents, or other bioactive molecules. The (3 + 1) tetrasubstituted adamantane building blocks display great potential for various biological applications, and different approaches can be followed to construct them (Figure 2): desymmetrization of tetrasubstituted derivatives (route 1), introduction in the remaining position of trisubstituted derivatives (route 2), or full bridgehead sites functionalization of monosubstituted derivatives (route 3) [98]. Despite the wide range of commercially available monosubstituted adamantanes at low price, no practical reactions following route 3 were explored yet. Maison and co-workers prepared a library of (3 + 1) building blocks with orthogonal functionalities including cyano, amino, carboxylic acid, hydroxyl, azido, alkyne groups linked with spacers of different lengths [26]. They proceeded via the partial hydrolysis of the tetramethyl ester 8 (route 1), via the monobromination of the semirigid tricarboxylic acid 27 (route 2), or via the monobromination of the 1,3,5-tri(phenyl)adamantane 18 using the PTC protocol (route 2) [95,98]. Selective acylation of the tetramethylamine 10 is also an example for the formation of (3 + 1) building blocks via route 1 [99]. Our group has developed a straightforward method to synthesize the 1,3,5-tricarboxy-7-aminoadamantane building block (34) (Scheme 3) [100]. Indeed, the 1-bromo-3,5,7-triphenyladamantane (31) obtained by monobromination of the triphenyl 18 (route 2) is a suitable substrate for the Ritter reaction using acetonitrile to give the corresponding N-acetylamide (32). Then, the oxidative degradation of the phenyl groups followed by acidic hydrolysis of the acetylamide function affords the water soluble and highly reactive (3 + 1) building block 34 bearing three carboxylic acids and one opposite amine. This scaffold offers the choice for direct attachment of ligands to preserve rigidity or the introduction of spacers to gain in flexibility. Moreover, its preparation in five steps starting from 1-bromoadamantane is performed with high yields without the need of silica gel column purification for each intermediate. This practical strategy allows the design of complex structures with a C3-symmetry,

Figure 2. Synthetic routes to form (3 + 1) tetrasubstituted adamantanebased building blocks. Modified from reference [98].

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a robust core, and an orthogonal position via protection/deprotection of the amine and the carboxylic acids groups. Dendritic Structures with an Adamantane Core Dendrimers have been investigated as ideal multivalent macromolecules for countless applications including those in medicinal chemistry [101,102]. Organic synthesis allows molecular engineering these hyperbranched architectures, so that many different types of dendritic scaffolds have been developed [103]. However, very few examples of these structures incorporate the adamantane motif. The first structure reported by Newkome et al. in 1992 was defined as a spherical cascade polymer derived from an adamantane core [104]. The synthesis of the first and second generation dendrimers bearing 12 and 36 branches, respectively, was performed via a divergent method starting from the tetracarboxylic acid 7 (Table 1). This four-directional cascade construction provided dendrimers with a tetrahedral adamantane nucleus orienting multiple flexible branches and with a polyester periphery which can be hydrolyzed quantitatively. Another type of more rigid dendritic adamantane-based scaffolds were constructed from the 1,3,5,7-tetrakis(4-iodophenyl)adamantane 13 (Scheme 1) to afford polyaromatic dendrimers [29,82]. Indeed, Pd-catalyzed cross-coupling reactions at the halogenated periphery of the adamantane scaffold led to the expansion of the tetrahedral structure with aromatic chains. Very recently, polyester-based dendrimers with an adamantane core have been synthesized using a combination of divergent and convergent routes [105]. First, two different tetraazido and tetraamino adamantane scaffolds were prepared via the formation of ester bonds starting from the 1,3,5,7-tetra(hydroxyl)adamantanol 11 (Table 1). Then, a divergent method made by successive Michael reactions on the peripheral amino groups of the tetraamino derivative led to the production of higher dendrimer generations with poor yields and the impossible isolation of pure products. A convergent route was therefore followed via the preparation of the dendritic polyester peripheries bearing an alkyne or a carboxylic acid function which were then conjugated to the corresponding tetraazido and tetraamino building blocks via click chemistry or coupling reactions, respectively. This strategy afforded the synthesis of the first, second, and third generation dendrimers with an adamantane core and polyester branches through low yields but with expected low cytotoxicity due to a biodegradable architecture [106]. In the way of a practical preparation of (3 + 1) adamantane building blocks, our group has designed a novel type of adamantane-based dendrons (wedge-shaped dendrimer sections) [100]. Boc-protection of the amine of the 1,3,5-tricarboxy-7-aminoadamantane building block 34 (Scheme 3) followed by coupling between the three carboxylic acids and three methyl-6-aminohexanoate chains provided the first generation dendron (35) bearing three alkyl chains terminated by a methyl ester group. Then, the synthesis of the second and third generations (36 and 37) was performed through a convergent route with high yields by playing with the protection/deprotection strategies of the Boc-protected amine and the methyl esters. In comparison with the previously described dendrimers, which incorporate one single molecule of adamantane in the core of the structure, this strategy led to the construction of dendrons with multiple adamantane motifs which were called HYDRAmers (Figure 3). Each layer of each generation presents tetrahedral adamantanes bearing alkyl chains via amide bonds, and the periphery consists of multiple methyl ester groups which can be easily hydrolyzed. The focal point affords an orthogonal position for further functionalization or for synthesis of larger generations. They were called with the Greek term Hydra because of the correlation of the second generation structure with the mythological

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Scheme 3. Synthesis of 1,3,5-tricarboxy-7-aminoadamantane building block [100].

Figure 3. Molecular structures of the first (35), second (36), and third (37) generation HYDRAmers built from a (3 + 1) building block. Adapted from reference [100].

serpent-like beast with nine heads. The potential cytotoxic effects of these HYDRAmers were evaluated on two different cell lines with concentrations up to 100 μM, and the data revealed that none of these dendrons affected the viability of the cells. Very recently, we described the synthesis and the characterization of new polyammonium and polyguanidinium HYDRAmers of different generations [107]. Tri- and tetraethylene glycol chains were used as flexible, water compatible branching units, and an alkyne group at the focal point was introduced to attach a fluorescent probe on the dendrons via click chemistry. These adamantane-based dendrons were well internalized by both phagocytic and non-phagocytic cells. In comparison with other polycationic carriers, they did not show cytotoxicity

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despite the presence of positive charges and their high cellular uptake. These results render HYDRAmers as promising adamantane-based molecules for future investigations in various biological applications. Biological Applications of Multivalent Adamantane Derivatives Multivalency is a common phenomenon in nature, and polyvalent interactions are characterized by the simultaneous binding of multiple ligands to multiple receptors [108]. The binding ability depends on several parameters including the size, the shape, and the valency of the multivalent agents. The central unit plays therefore an important role in the efficacy of the biological activity. The rigid

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GRILLAUD AND BIANCO well-defined 3D conformation of adamantane core with four functionalizable bridgehead positions provides multi-functional adamantane-based scaffolds as good candidates for various biological applications. Despite the number of reviews related to the use of adamantane derivatives for biomedicine [14–21], few examples using multivalent scaffolds are currently reported likely because of their very recent design and synthesis. A series of adamantane-based trimeric benzoboroxoles were prepared and they are now ready for future biological investigations as carbohydrate binders (Figure 4) [109]. This small collection of lectin mimetics with different numbers and spacings of benzoboroxole moieties on multi-functionalized adamantane scaffolds was synthesized via click chemistry. The resulting conjugates have been labeled with fluorescent dyes and were conjugated to peptides as additional recognition motifs. Besides this preparation of labeled adamantane derivatives, it has been demonstrated that fluorescent labels containing multiple fluorescein moieties attached to adamantane were able to present amplified fluorescent signal [110]. Indeed, the adamantane core prevented fluorescein moieties from intramolecular proximity and interaction, thus precluding mutual fluorescence quenching, which often occurs for planar aromatic molecules bearing multiple fluorophores. Adamantane Conjugated Peptides as Ligands for Binding Cell Surface Receptors Among the receptor ligands for imaging and radiotherapy, peptides involving the RGD (arginine–glycine–aspartic acid) motif are an attractive class of peptide-based ligands for recognition of the members of the integrin receptor family. The latter participates in angiogenesis, tumor growth, and metastasis, and this type of receptors is mainly located on the surface of endothelial cells [111]. The radioiodinated c(RGDyV) cyclic peptide was shown to display an efficient capacity to image integrin receptors [112] and it has been conjugated to different scaffolds, including adamantane, in order to assess the multivalent ligand behavior for binding to U87MG cells expressing αvβ3 integrins (Figure 5) [113]. The relative binding affinities of the multivalent ligands to the cells including c(RGDyK) and echistatin as controls were determined by competition assays with tyrosine 125I-labeled echistatin. The increasing number of RGD peptide ligands bound around terephthalic acid, trimesic acid, and 1,3,5,7adamantane tetracarboxylic acid 7 scaffolds revealed an increase of binding avidity evidenced by decreasing inhibition constant Ki values. Ethylene glycol (EG) chains of different lengths were introduced as

Figure 4. Molecular structures of different adamantane-based trimeric benzoboroxoles synthetized via ‘click’ chemistry. Adapted from reference [109].

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linkers between the core and the ligand (EG3 and EG6), and the Ki values increased with the lengths of the linkers throughout the dimeric, trimeric, and tetrameric RGD derivatives. The calculated Ki (c(RGDfK)/Ki (multimer) ratios indicated the increase of affinity as a result of multimerization in relation to the monovalent c (RGDyK), with the highest values using adamantane scaffold 7. The results also illustrated the detrimental influence of EGn spacers. From these data, the tetra-functional adamantane derivative 7 bearing the highest number of RGD motifs offered the best binding avidity to αvβ3 integrin-expressing cells in comparison with the other planar dimer and trimer showing the importance, the 3D central core, and the multivalency for cell surface binding (Figure 3). Moreover, the insertion of flexible linkers displayed lower interactions with the cell receptors meaning that the rigidity is also a parameter to be taken into account for the design of multivalent ligands. Tumor necrosis factor-α – related apoptosis – inducing ligand (TRAIL) has resulted as an interesting molecule in cancer therapy due to its unique characteristic to induce apoptosis in tumor cells without affecting normal cells [114]. TRAIL receptors belong to the subgroup of tumor necrosis factor (TNF) receptors that contain an intracellular ‘death domain’ and induces apoptosis. Trimerization or multimerization of the two fully functional receptors TR1 and TR2 affords a death-inducing signaling complex, which led to caspase activation and cell death [115,116]. Small apoptogenic cyclic peptides were developed to specifically recognize TR2. Once in an oligomeric form, they mimic the function of the natural ligand TRAIL. Some of these TRAIL-mimicking peptides were investigating to bind TR2, and the receptor affinity was evaluated by comparing the monovalent peptides, the divalent peptides obtained by dimerization using bis-succinimidyl carboxymethoxyacetate, and the trivalent system based on a semi-rigid adamantane building block as central core [117]. Surface plasmon resonance experiments in which recombinant human TR2 (rhTR2) was immobilized on a sensor chip and allowed to interact with the different ligands showed that the different monovalent peptides bind to rhTR2 with micromolar affinity. The divalent peptides significantly improved the binding affinity to rhTR2 (i.e., 100-fold to 6.000-fold), and only one trivalent derivative resulted in a 45-fold increased affinity to rhTR2 relative to the corresponding divalent form. Similar investigations were performed by our group to study the multimerization effect of one of these apoptogenic cyclic peptides on TR2 binding by using different generations of adamantane-based dendrons as multivalent scaffolds [118]. The peptide ligand, that we called M1, was conjugated to the HYDRAmers leading to the formation of a trimeric (42) and a hexameric (43) dendron (Figure 6). rhTR2 and the mouse homologue of TR2 were immobilized on a sensor chip, and the peptide–adamantane ligands were allowed to interact with the receptors at different concentrations to measure the affinity constants. All compounds showed specific binding to human TR2, whereas there was no interaction in the case of murine TR2. The experiment using the first generation dendron devoid of the peptide allowed confirming that the ligand/receptor interaction was not influenced by the adamantane core. The ligand in its trivalent form substantially improved the binding affinity to human TR2 by approximately 1500-fold in comparison with the monomer, and the hexamer 43 displayed a 14-fold increased affinity to human receptor relative to the trimer 42 (Figure 6). The higher binding affinity of the multivalent ligands compared with the monomeric peptide was influenced by a high decrease in the dissociation kinetic rates (koff), whereas the association rates (kon) were similar to that of the monomer M1. These results can be explained as an enhanced stability of the ligand/receptor complex due to the multimerization of peptide M1 that provided a multivalent interaction with TR2.

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Figure 5. Structures of the different scaffolds, linkers, and multivalent RGD derivatives. Graph A: Ki values of c(RGDyK), echistatin, and RGD multimers. 125 Competition was performed against [ I]echistatin on U87MG cells. Mean ± SD; NS = not significant; *P < 0.05, unpaired t-test. Graph B: Ki (c(RGDfK))/Ki (multimer) ratios of RGD multimers. Data were expressed as mean ± SD. Reproduced with permission [113]. Copyright 2010, Elsevier Ltd, Amsterdam.

Figure 6. Structures of the trimer and the hexamer peptide HYDRAmers and kinetic parameters of the M1 ligand in its monovalent, trivalent (42), or hexavalent form (43). Reproduced with permission [118]. Copyright 2013, Wiley-VCH Verlag GmbH & Co.

The analysis of the efficiency and specificity of the multivalent peptide–adamantane ligands to trigger cell apoptosis in a TR2dependent manner was then performed on an in vitro model of

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human Burkitt lymphoma (BJAB). We used cells that either express or do not express (BJAB TR2+ or BJAB TR2 cells, respectively) TR2. A significant death of BJAB TR2+ cells was observed using both trimer

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GRILLAUD AND BIANCO and hexamer, whereas viability of BJAB TR2 cells was not affected, thus indicating high TR2 selectivity of the multivalent peptides. The monomeric peptide M1 did not induce apoptosis on BJAB TR2+ cells, confirming that a multivalent form of the peptide is necessary to trigger a substantial TR2-dependent apoptotic response in vitro. Surprisingly, the hexamer 43 showed a decreased biological activity (i.e., cell death) relative to the trimeric ligand 42. This result was probably because of unfavorable interactions between the six M1 peptides of the hexamer and TR2 at the cell surface for reasons of steric hindrance. These two studies highlight how adamantanebased dendrons can be promising scaffolds because of their 3D tripodal arrangement for the multimerization of peptides. The specific receptors on the cell surface have also attracted considerable attention as tumor markers. In this context, diverse small molecules have been developed with high affinity binding to prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein overexpressed on malignant prostate cells and their metastases [119]. The (2[(3-amino-3-carboxypropyl)(hydroxy) (phosphinyl)-methyl]pentane-1,5-dioic acid) molecule (abbreviated GPI), which is negatively charged at pH = 7 and which has an affinity constant of 9 nM for the active site of the tumor marker PSMA, was conjugated to a (3 + 1) adamantane building block as multimeric cell surface binder for prostate tumor targeting [120,121]. The first study using this multivalent system focused on single photon emission computed tomography imaging, a nuclear medicine technique by which γ-ray emissions from a radioisotope are used to localize cancer. One of the main radioisotopes clinically used is 99mTc. Maison and co-workers have developed a simple and rapid cartridge-based method for converting readily available and inexpensive 99mTcpertechnetate (Na99mTcO4) into a chemically pure, reactive NHS ester in organic solvent [121]. This method allowed the preparation of the radiotracer in ultrapure form in only 25 min, with an overall radiochemical yield up to 75% relative to 99mTc-pertechnetate starting material. Then, the adamantane-based scaffolds bearing one (44), two (45), or three (46) GPI were labeled with the 99mTc radiotracer in one chemical step, and no further purification was necessary (Figure 7). The affinity of each negatively charged GPI-containing radiotracer for the surface of living prostate cancer cells was measured. The data from the assay using the monomers (single GPI conjugated with the radiotracer and adamantane-based monomer 44) and the trimer 46 (adamantane scaffold bearing three GPI) demonstrated that both high

concentrations of phosphates in PBS buffer and serum competed effectively with monomers for the active site of PSMA but were unable to compete with the trimer 46. Indeed, the latter displayed identical affinities under all physiologic conditions. Conjugation of a single GPI monomer to a single adamantane core had only a negligible effect on the affinity, whereas increasing multivalency from one to three led to remarkable improvements in both affinity constant and competition with anions of buffers and serum. The final affinity of the trimer 46 was equivalent to that of some PSMA monoclonal antibodies. These results render multivalent GPI-containing radiotracers good candidates for single photon emission computed tomography imaging assessments. Alternatively, these adamantane-based scaffolds were also used in prostate cancer imaging using near-infrared (NIR) fluorescence, invisible to the human eye but with a high transmission capacity through living tissues [120]. For this purpose, an NIR dye was conjugated to the different scaffolds (47, 48, and 49) and to the single GPI instead of a radiotracer (Figure 7). The data from the affinity assay using monomeric versions of GPI confirmed previous finding that high concentrations of phosphate in PBS buffer and serum competed efficiently for the active site of PSMA. In contrast, dimeric 48 and trimeric 49 GPI conjugates displayed almost the same binding affinities to LNCAP cells (PSMA+) in TBS and PBS buffers and even in serum. It was also shown that affinities of PSMA ligands were not dependent on the nature of the dye or its linker moiety around the adamantane core. The binding of NIR-labeled GPI and trimer 49 to endogenous PSMA on the cell surface was studied using in vitro NIR fluorescence imaging. Only the trimeric version of GPI 49 bound to 100% of the PSMA+ cells. All these results confirm the potential applications using multivalent adamantane-based scaffolds, functionalized with peptides or small molecules, involving cell surface receptor interactions, particularly targeting tumors. Another interesting example, where multi-functionalized adamantane was combined to proteins, short peptides, and haptens, aiming to develop new vaccine formulations appeared very recently [122]. Indeed, a therapeutic strategy currently in clinical development to fight smoking problems is vaccination against nicotine. Anti-nicotine antibodies are generated to sequester nicotine, thus preventing it from binding to nicotinic acetylcholine receptors in the brain. In this context, it has been developed a strategy to present multiple copies of a hapten (a hapten is a small molecule that can

Figure 7. Structures of the labeled GPI-containing adamantane-based scaffolds for prostate tumor imaging. Adapted from references [120,121].

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MULTIFUNCTIONAL ADAMANTANE elicit an immune response only when attached to a large carrier such as a protein) to B cells using a multivalent adamantane-based scaffold [122]. The increase of the copies of the hapten conjugated to a carrier protein surface (hapten density) is generally correlated with an increase in the immune response strength and specificity. For this purpose, 3′-substituted nicotine-hapten AM1, used in the majority of nicotine vaccines that have progressed furthest through clinical trials, was selected (Figure 8). The use of multivalent presentation as a mean to tailor drug hapten density and clustering was examined in the context of drug-immune response modulation. The trivalent hapten with an adamantane core containing a diglycine spacer, triAM1(Gly)2, was synthesized and conjugated to OVA (50). This conjugate was able to elicit anti-nicotine antibodies at equivalent affinity and concentration to the monovalent AM1 analog, although the latter had a lower hapten density. Indeed, triAM1(Gly) 2-OVA 50 induced the generation of antibody with concentration and affinity similar to AM1-OVA after 56 days post-injection, suggesting that the immune system was able to successfully recognize both the monohapten units or its trimeric form. Unexpectedly, the corresponding monovalent hapten AM1(Gly)2 coupled to OVA resulted instead in an enhanced antibody affinity in comparison with the trimer. A direct comparison between triAM1(Gly)2-OVA 50 and AM1(Gly)2-OVA led to formulate the hypothesis that the trivalent scaffold will likely require additional molecular engineering including optimization of the peptide linker and protein conjugation chemistry to gain in activity in comparison with the monomer. However, the use of adamantane scaffold for vaccine purposes looks promising.

Delivery of Small Drugs and Therapeutic Peptides using Adamantane-based Dendrons Our group has explored the use of multifunctional adamantanebased dendrons as new carriers for small drugs and therapeutic peptides. We have initially exploited the multivalency effect of the HYDRAmers on the activity of the anti-inflammatory drug, ibuprofen, on lipopolysaccharide-stimulated murine macrophages [123]. For this purpose, we performed the functionalization of the periphery of the first and second generations (G1 and G2) adamantane-based

dendrons with ibuprofen (called Ibu-HYDRAs). This approach allowed to obtain the corresponding conjugates bearing the drug in trimeric (51) or nonameric (52) form, respectively (Figure 9). It is known that ibuprofen mediates inflammatory processes by inhibiting the cyclooxygenase enzyme and consequently prostaglandin production. This behavior affects the formation of pro-inflammatory cytokines such as TNF alpha (TNFα) and interleukin 6 (IL6) both in vitro and in vivo. The anti-inflammatory effect of the Ibu-HYDRAs was evaluated by quantifying the inhibition of production of cytokines on RAW 264.7 macrophages and further extended the analysis to primary intraperitoneal murine macrophages. We measured a higher anti-inflammatory activity of Ibu-HYDRAs in comparison with non conjugated ibuprofen. This observation was attributed to a better availability of the multivalent ibuprofen compared with the drug alone. This hypothesis was consistent with the fact that the second generation Ibu-HYDRA 52 was more efficient in reducing TNFα and IL6 production than the first generation Ibu-HYDRA 51 and free ibuprofen. It is possible that the multivalency permitted the interaction of ibuprofen with more than one intracellular target at the same time leading to an increase in the anti-inflammatory response. This encouraging proof of concept highlights the promising application of multivalency to other therapeutic molecules. In this context, we extended the use of HYDRAmers to the multipresentation of peptides. P140 is a therapeutic peptide with protective properties in systemic lupus erythematosus, a multiorgan autoimmune disease [124]. This peptide corresponds to the fragment 131-151 (RIHMVYSKRSGKPRGYAFIEY) of the spliceosomal U1-70K small ribonucleoprotein and contains a phosphorylated serine at position 140. Intravenous administration of P140 peptide to lupus-prone MRL/lpr mice reduces blood hypercellularity, attenuates autoimmune manifestations, including proteinuria, vasculitis, dermatitis, anti-double-stranded DNA antibody level, and prolongs the survival of the animals [124–126]. This phosphopeptide is also able to decrease the severity of the symptoms severity in lupus patients, as demonstrated by phase II clinical trials [127,128]. Following in vivo administration, it was shown that P140 binds to HSPA8/HSC70 chaperone protein and rapidly accumulates in the spleen [129]. To further explore the potential of P140 and

Figure 8. Structures of AM1, AM1(Gly)2, and triAM1(Gly)2 (50) synthesized to elicit anti-nicotine antibodies. Adapted from reference [122].

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GRILLAUD AND BIANCO

Figure 9. Molecular structures of G1 Ibu-HYDRA (51), G2 Ibu-HYDRA (52), and ibuprofen alone. Adapted from reference [123].

create a multimeric system, two peptides, the therapeutic P140 and the biologically ineffective scrambled sequence ScP140, were covalently attached to an adamantane scaffold (Figure 10). The properties of the corresponding trimers (53 and 54) were studied in comparison with the monomers [130]. Initially, we found that the trimerization of P140 did not trigger aggregation and did not affect its binding affinity to the HSPA8 protein. Even though P140 was covalently linked to the adamantane-based dendron through its Nterminal position via an additional cysteine, the peptide recognition site was readily available to interact with HSPA8. Using surface plasmon resonance experiments, we measured similar dissociation rates, suggesting that the stability of the ligand/receptor complexes was conserved in the trivalent form of P140 53. Moreover, these analyses proved that the trimerization of the peptide did not create a sterical hindrance between each peptide chain of

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the dendron that might have prevented the peptide interaction with the protein. As the molar mass of adamantane scaffold is very low (1125.7 g · mol 1) compared with the molar mass of P140 trimer 53 (9349.6 g · mol 1), the trimerization of the peptide did not alter the formation of the complex with HSPA8 probably because of the 3D conformation of adamantane and the tripodal arrangement of adamantane-based scaffold. In addition, the P140 trimer 53 impaired HSPA8 folding property with a reducing effect of 47% and 75% at 20 and 40 μM, respectively, whereas P140 displayed an inhibitory effect of only 3% at 20 μM and 29% at 40 μM (Figure 10). Although ScP140 showed no effect at the different concentrations tested, its corresponding trimer 54 reduced HSPA8 activity by 37% at 20 μM and 56% at 40 μM demonstrating unspecific interactions triggered by the trimerization of ScP140. The different adamantane P140 and

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Figure 10. Structure of the trimeric P140 and ScP140 using an adamantane-based scaffold and their capacity to hamper HSPA8 chaperone properties in vitro in comparison with the monomers. Heat-denatured luciferase was refolded during 1 h at 30 °C with rabbit reticulocyte lysates, in the presence of increasing concentrations of P140, ADA-P140 (53), ScP140, or ADA-ScP140 (54). The indicated doses correspond to the molar concentrations of peptide, either single or coupled to adamantane-based dendrons. Reproduced with permission [130]. Copyright 2014, Elsevier Ltd, Amsterdam.

ScP140 trimers were also tested in vivo on lupus-prone MRL/lpr mice, and both displayed effective reduction of white blood cells. This decrease was significantly higher with the trimer 53 at 100 μg of peptide injected compared with the monomer. No effect on blood hypercellularity of MRL/lpr mice was observed using ScP140 and its trivalent form 54, although the latter impaired HSPA8 activity in vitro. The unique structural properties of adamantane and the results of this work show how adamantanebased dendrons result as promising scaffolds for the attachment of therapeutic peptides. This trivalent system could be highly attractive for other biomedical applications involving biological recognition processes.

Acknowledgements

Conclusions Among the number of adamantane derivatives exploited in medicinal chemistry, the recent design of multi-functionalized adamantane scaffolds represents promising multivalent structures for biological and biomedical purposes. The inexpensive molecule of adamantane can be substituted in one to four bridgehead positions in multigram scale to provide a wide range of poly-functional derivatives. Molecular engineering on adamantane building blocks can lead to the construction of complex structures with a rigid core, which can combine both multivalency and C3-symmetry. Moreover, the properties of these

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scaffolds can be tuned at each step of the organic synthesis, and the final structures can display a tripodal or a tetrahedral geometry. The diverse recent biological studies illustrate the high potential of multivalent adamantane-based systems in the biomedical field including interactions with receptors at the cell surface and the delivery of drugs. The design of multivalent adamantane-based scaffolds, modified with bioactive peptides, seems to be a great example to corroborate the interesting results obtained on multimerization of binding peptide epitopes into an optimally spaced rigid structure. All these investigations support the idea to design and synthesize novel multi-functionalized adamantane-based peptides for applications spanning the domains of life and materials science.

We acknowledge the financial support of Centre National de la Recherche Scientifique (CNRS) and M. G. would like to thank the International Center for Frontier Research in Chemistry (icFRC) and the Région Alsace for financing his PhD.

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J. Pept. Sci. 2014

Multifunctional adamantane derivatives as new scaffolds for the multipresentation of bioactive peptides.

The remarkable structural and chemical properties of adamantane afford attractive opportunities to design various adamantane-based scaffolds for biome...
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