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Engineering CNDP’s of dendrimers containing phosphorous interior compositions to produce new emerging properties

  • Anne-Marie Caminade
  • Jean-Pierre Majoral
Review
Part of the following topical collections:
  1. Unifying Concepts for Nanoscience and Nanosystems: 20th Anniversary Issue

Abstract

Phosphorus-containing dendrimers are defined as dendrimers having at least one phosphorus atom at each branching point. In this review, we will show how phosphorhydrazone dendrimers can be modified at will at the level of the core and of the branches, to afford specific properties, such as fluorescence to image biological events. Accelerated methods of synthesis of phosphorus (one step for one generation) will be also displayed, as well as the specific reactivity of P=N–P=S linkages obtained in most of these accelerated method of synthesis, which has led to particularly original dendritic architectures, such as dendrons included in dendrimers. Finally, we will display how modifications of the internal structure of a series of dendrimers having the same type and number of terminal functions can deeply modify their biological anti-inflammatory properties. Among the six critical nanoscale design parameters (CNDP), we will show how two of them, i.e., architecture and elemental composition, have been particularly engineered to modify phosphorus-containing dendrimers, in order to fulfill the desired properties.

Keywords

Phosphorus chemistry Monomers Dendrimers Fluorescence CNDP Nanoscale architectures 

Introduction

Prof. Donald A. Tomalia has proposed in 2009 (Tomalia 2009) the concept of CNDP (critical nanoscale design parameters) for unifying and defining nanoscience. Six parameters have been defined, concerning (i) size, (ii) shape, (iii) surface chemistry, (iv) flexibility/rigidity, (v) architecture, and (vi) elemental composition of nano-objects. The CNDP can be applied to both hard (metal-based) nanoparticles and soft (organic-based) nanoparticles, and is of interest for both chemists and physicists (Tomalia and Khanna 2016). Among all nanosized objects, dendrimers occupy a special place. This word has been created by Prof. Donald A. Tomalia from two Greek words δέντρο (dendro), which translates to “tree”, and μέρος (meros), which translates to “part”, and has been used since a long time in “polymers” (Tomalia et al. 1986). The CNDP concept is particularly well adapted to the definition and properties of dendrimers, which are soft nano-objects. Indeed, the step-by-step synthesis (Fig. 1) allows to control and finely tune all these critical parameters (Tomalia 2010; Tomalia 2012), in connection with their properties, as for instance for their use in nanomedicine (Kannan et al. 2014).
Fig. 1

Principle of the step-by-step synthesis of dendrimers, up to the fourth generation

In this review, we will consider in particular how the two last parameters (architecture and elemental composition) may influence the properties of phosphorus-containing dendrimers, which are defined as dendrimers having at least one phosphorus atom at each branching points. We will show first how the synthesis of phosphorhydrazone dendrimers can be modified at will at the level of the core and of the branches, in particular not only to incorporate linkages that are able to be modified after the synthesis of the dendrimers, leading to unprecedented architectures, but also to improve the synthesis by decreasing the number of steps for a given number of terminal functions. We will show also how the modifications of the internal structure may deeply modify the biological properties, even with identical terminal functions.

Synthesis of phosphorhydrazone dendrimers

The most widely used method of synthesis of phosphorus-containing dendrimers consists in the repetition of a two-step process, using successively 4-hydroxybenzaldehyde in basic conditions and the phosphorhydrazide H2NNMeP(S)Cl2 (Fig. 2). Both steps generate only NaCl and H2O as by-products, are quantitative, and can be applied starting from different cores. Starting from P(S)Cl3 (Fig. 2a), this process was carried out first up to the fourth generation (Launay et al. 1994), then up to the seventh generation (Launay et al. 1995), to the tenth generation (Slany et al. 1995, 1997), and finally to the twelfth generation (Lartigue et al. 1997), which was the highest generation well characterized obtained for any type of dendrimers up to 2013 (Lim et al. synthesized the thirteenth generation of triazine dendrimers in Lim et al. 2013). Starting from the hexafunctional core N3P3Cl6 (Fig. 2b), the reactions were first carried out up to the fifth generation (Slany et al. 1995), then up to eighth generation (Launay et al. 1997), which is presumably not the highest generation obtainable from this hexafunctional core. Using N3P3Cl6 instead of P(S)Cl3 affords twice the number of terminal functions at each generation. For instance, at the level of the third generation, the dendrimer built from the P(S)Cl3 core has 24 Cl as terminal functions, whereas the dendrimer built from the N3P3Cl6 core has 48 Cl at the same generation (Fig. 2).
Fig. 2

Synthesis of phosphorhydrazone dendrimers. a From the trifunctional core S=PCl3. b From the hexafunctional core N3P3Cl6. In both cases, the full structure is represented only for the first steps, and then the structure is represented with parentheses after each branching point

This method of synthesis is compatible with numerous types of modifications of the internal structure, in particular by replacing 4-hydroxybenzaldehyde by other hydroxyl aldehydes, even hydroxyl dialdehydes, and other types of dialdehydes. We will display in the next paragraphs how these modifications influence the properties of these dendrimers.

Internal functionalization of phosphorhydrazone dendrimers, and influence on the properties

Electrochemical properties of phosphorus dendrimers with ferrocenes in the internal structure

Replacing 4-hydroxybenzaldehyde by a ferrocene functionalized by a phenol and an aldehyde at one or several layer affords the opportunity to study the electrochemical properties of these dendrimers. Both functions can be on the same cyclopentadienyl ring of the ferrocene (affording chiral derivatives), or one function on each cyclopentadiene. Figure 3 displays the synthesis of a series of dendrimers possessing ferrocene units at each generation, and the electrochemical traces of each compound. The cyclic voltammogram of generation zero (G 0 -Fe 3 ) displays a single reversible oxidation of the three ferrocenes to ferroceniums. The first generation (G 1 -Fe 9 ) has ferrocenes at two levels, in a different environment; thus, two waves are expected and indeed observed: one for the 6 ferrocenyl aldehydes, analogous to the one observed for G 0 -Fe 3 , and another wave, corresponding to the 3 ferrocenyl hydrazides, having an increased electronic density. The second generation (G 2 -Fe 21 ) has three levels of ferrocenes, but only two different types of environments (12 ferrocenyl aldehydes and 9 ferrocenyl hydrazides) and two waves are indeed observed (Fig. 3) (Turrin et al. 2000). The same behavior was observed with another family of ferrocenyl phosphorhydrazone dendrimers (Turrin et al. 2002a).
Fig. 3

Synthesis of phosphorhydrazone dendrimers incorporating ferrocenes at all layers, and traces of their electrochemical behavior

It is also interesting to consider the ferrocene as a sensing element. For this purpose, chiral ferrocenes (Turrin et al. 2001) have been incorporated at a single layer in the phosphorhydrazone dendrimers, to detect the influence of the burying inside the structure, both by electrochemistry and by measurement of the chiroptical properties. Three series of compounds have been synthesized, in which the chiral ferrocenes have been incorporated either at the level of the third generation (Fe 24 @G 3 ), or at the level of the fifth generation (Fe 96 @G 5 ), or even at the level of the ninth generation (Fe 1536 @G 9 ). In the three cases, the growing of two additional generations has been carried out, affording Fe 24 @G 5 , Fe 96 @G 7 , and Fe 1536 @G 11 , respectively (Fig. 4a, b). The electrochemical response of the ferrocene layer is displayed in Fig. 4c for the series of dendrimers possessing the ferrocenes at the level of the fifth generation (Fe 96 @G 5 , Fe 96 @G 6 , and Fe 96 @G 7 ). As shown in the previous case, the replacement of the aldehydes by the hydrazine linkage (Fe 96 @G 5  → Fe 96 @G 6 ) induces a shift towards anodic potentials. Another phenomenon is observed on going from Fe 96 @G 6 to Fe 96 @G 7 , i.e., a decrease of the rate of the electronic transfer, inducing a decrease of the intensity of the wave (Fig. 4c). Furthermore, the reversibility of the system decreases as the generation of the dendrimer increases, Fe 1536 @G 11 being the least reversible system. All these phenomena can be explained by a decrease in the accessibility of the ferrocenes to the electrode (Turrin et al. 2002b). An analogous phenomenon has been observed for small water-soluble ferrocenyl dendrimers (de Jong et al. 2012), due to the shrinkage of the phosphorhydrazone dendrimers in water (Leclaire et al. 2004).
Fig. 4

a Synthesis of three families of dendrimers possessing a single ferrocene layer. b Chemical structure of the dendrimer of generation 5, possessing 24 ferrocene groups at the level of the third generation. c Cyclic voltammograms of the family of dendrimers possessing 96 ferrocenes at the level of the fifth generation. d Molar rotation values divided by the number of chiral entities for the three families of dendrimers, displaying the large difference between the aldehyde and the hydrazine terminal functions

We have also studied the chiroptical properties of all the dendrimers of type Fe x @G n in which the chirality of the ferrocene is afforded by the presence of two substituents on the same cyclopentadiene (planar chirality). We have measured the optical rotation for all three families of dendrimers. The values of [αD] (specific rotation) depend almost exclusively on the chemical environment of the chiral ferrocenes, and not on the generation considered. Indeed, a dramatic change in [αD] is observed on going from the aldehyde to the hydrazone substituents of the ferrocenes. The molar rotation values [αmol] divided by the number of chiral entities are a constant for all series having the same chemical environment, for instance Fe 24 @G 3 , Fe 96 @G 5 , and Fe 1536 @G 9 (or Fe 24 @G 5 , Fe 96 @G 7 , and Fe 1536 @G 11 ). On the contrary, [αmol] divided by the number of chiral entities is very sensitive to changes in the chemical environment, from Fe x @G n to Fe x @G n + 1 (aldehyde → hydrazone) (Fig. 4d) (Turrin et al. 2002b).

Recently, this fundamental work on ferrocenyl dendrimers has led to an original application in catalysis. A series of dendrimers with ferrocenyl groups close to the surface, and bearing a phosphine as substituent and terminal function, either linked directly to a cyclopentadiene, or linked through a phenyl (C6H4) or a biphenyl (C6H4-C6H4) group has been synthesized, and the corresponding ruthenium complexes have been tested as catalysts for the isomerization of allyl alcohols to ketones (Fig. 5c). The dendrimers with the C6H4 linker are the most efficient (Neumann et al. 2015b). The first generation of these dendrimers is shown in Fig. 5a. As for other dendrimers, the ferrocenes can be easily and reversibly oxidized to ferroceniums. It can be noted that Ru can be also oxidized but at a different and well separated potential, as shown by electrochemistry. The specific oxidation of the ferrocene can be carried out also chemically, by choosing the adequate oxidant and reductant, to oxidize and reduce the ferrocenes, without interfering with the RuII redox process. [Fe{η5-C5H4C(O)Me}Cp][BF4] was chosen as the oxidant, and [FeCp*2] (Cp* = pentamethylcyclopentadiene) as reductant, as illustrated in Fig. 5a. The same process has been carried out with the corresponding monomer (Fig. 5b). The oxidation of the ferrocenes should modify the electronic environment of the phosphine and of the ruthenium, by an electronic communication through the aromatic linker, thus potentially interfering in the catalytic process shown in Fig. 5c. Indeed, the reaction rate is high in the presence of the neutral dendrimer (higher than when using the same quantity of monomer) but decreases dramatically when the ferrocenes are oxidized. The switching is reversible, as almost the same rate as at the beginning is recovered after reduction of the ferroceniums to ferrocenes, demonstrating a switch ON-OFF-ON process (Fig. 5c). This is the first example of a redox-switchable isomerization of an allylic alcohol, and the very first example of a dendrimer used in a redox-switchable catalysis (Neumann et al. 2015a).
Fig. 5

a Chemical oxidation and reduction of a first generation ferrocenyl phosphine dendrimer ended by phosphino-ruthenium complexes. b Oxido-reduction of the corresponding monomer. c The reaction catalyzed by the dendrimer and monomer. d Comparison of the experimental rate constant of the monomer and of the dendrimer, and depending on the oxidation state of the ferrocene

Fluorophores in the internal structure of phosphorhydrazone dendrimers, and their use in biology

Different types of fluorophores have been incorporated inside phosphorhydrazone dendrimers, either at the core, or linked to the core (off-center), or as constituents of the branches, by replacing 4-hydroxybenzaldehyde, as already shown above in the case of ferrocenes. In most cases, the terminal functions are modified to ensure the solubility in water, in view of biological experiments (Caminade et al. 2009).

Fluorophores used as core of phosphorhydrazone dendrimers

Any type of compound having either aldehydes or P-Cl2 functions can be used as core of phosphorhydrazone dendrimers. Both cases have been exemplified for incorporating fluorescent groups inside dendrimers. In a first example, a phthalocyanine functionalized by eight aldehydes (Fig. 6a) was used for the growing of phosphorhydrazone branches up to generation 4 with aldehyde terminal functions, and up to generation 5 with ammonium terminal functions. The phthalocyanine at the core of the dendrimers with aldehyde terminal functions was used as a probe for characterizing the influence of the branches, which exert the same influence to the core than a polar solvent like DMF (Leclaire et al. 2005). With ammonium terminal functions, the dendrimer has a hydrophobic interior, and a hydrophilic surface. It is shrunk in water but behaves as a nanometric sponge when increasing amounts of THF are added to water, as shown by the increase of its size, from R H  = 6 nm in pure water to R H  = 8.2 nm in water/THF, as measured by DOSY NMR (Leclaire et al. 2004). Some biological properties of the same dendrimer were tested. It showed a moderate cytotoxicity towards HeLa (human epithelioid cervical carcinoma cells line), HEK 293 (human transformed primary embryonal kidney cells line), and HUVEC (human umbilical vein endothelial cells) cells. This dendrimer efficiently delivered fluorescein-labeled oligodeoxyribonucleotide, as well as a DNA plasmid containing the functional gene of the EGFP (enhanced green fluorescent protein), in HeLa cells in the presence of serum, demonstrating its efficiency as transfection agent (Maszewska et al. 2003).
Fig. 6

Types of fluorescent cores for the synthesis of phosphorhydrazone dendrimers with ammonium terminal functions. a Phthalocyanine core, for dendrimers synthesized up to the fifth generation, and used for transfection experiments. b Two-photon excited fluorophore as core of phosphorus dendrimers up to the third generation, and used for in vivo imaging of a rat olfactory bulb vessels. c Longer two-photon excited fluorophore used to build dendrimers up to the second generation, for imaging the vascular network of a tadpole

The two-photon (2P) excited fluorescence is based on the simultaneous absorption of two photons instead of one photon in standard excitation, to reach the excited state of the fluorophore, subsequently leading to fluorescence emission. A focussed fluorescence and a deeper penetration in biological tissues are observed with this method; thus, it is particularly interesting for in vivo imaging. Specially engineered fluorophores having two-photon absorption properties (Fig. 6b, c) were linked to two triphosphazene rings as core of phosphorhydrazone dendrimers. The second generation of the dendrimer having the fluorophore shown in Fig. 6b as core and ended by ammonium groups has been used for imaging in vivo the vascular network of a rat olfactory bulb (Krishna et al. 2006). The same core was used to build dendrimers having another two-photon fluorophore as terminal functions, and to study the interactions between the core and the surface, depending on the generation (G0–G2) (Mongin et al. 2007). With a longer core (Fig. 6c), and ammonium water-solubilizing terminal functions, the phosphorhydrazone dendrimer was used for studying its fluorescence, depending on the solvent (Rouxel et al. 2012), and for imaging in vivo the vascular network of a tadpole (Mongin et al. 2008).

Fluorophores used as branches of phosphorhydrazone dendrimers

The two-photon excited fluorophores have been used also as branches of phosphorhydrazone dendrimers, in replacement of 4-hydroxybenzaldehyde, in view of imaging different biological events. Figure 7a displays a blue emitting fluorophore, which has been incorporated at the level of the first generation, in a third generation dendrimer ended with ammonium groups, and in a second generation dendrimer ended by PEG (polyethylene glycol) (Mongin et al. 2009). The green emitting fluorophore shown in Fig. 7b has been also incorporated at the level of the first generation of a second-generation dendrimer, having ammonium terminal functions. This dendrimer was well retained by bone marrow macrophages and was used to identify the presence of macrophages and phenotype status after spinal cord injury of mice (Shakhbazau et al. 2015). An analogous dendrimer, but having both PEG and pyridine-imine copper complexes as terminal functions, was used to get insights in the mode of action of the corresponding non-fluorescent dendrimers (El Brahmi et al. 2013) against cancerous cell lines (Mignani et al. 2017).
Fig. 7

a, b Two-photon excited fluorophores used as branches at the level of the first generation of second generation water-soluble dendrimers. c Azobenzene incorporated at one or all layers of phosphorhydrazone dendrimers, for studying the trans-cis-trans isomerization

A related hydroxyl aldehyde is the azobenzene derivative shown in Fig. 7c. This azobenzene was incorporated either at the level of the first generation, and the dendrimer was built up to the third generation, or at all layers, also up to the third generation. The fluorescence properties of these compounds were not studied, but the photo-induced trans → cis isomerization of the azo groups and their thermal cis → trans isomerization in the dark were studied, mainly by NMR (Deloncle et al. 2008). The relative amount of cis and trans isomers obtained at the photostationary equilibrium differs largely, depending on the location of the azobenzene groups: The more the azobenzene groups are buried inside the dendrimer, the more they are reluctant to isomerize (Sebastian et al. 2002).

Fluorophores linked “off-center” to the core

Another way to have a fluorophore in the internal structure of dendrimers consists in using one function of the core to graft the fluorophore, and to use the other functions to continue the growing of the branches, as for a “normal” regular dendrimer. Such methodology is called “off-center” and is especially useful when applied to hexachlorocyclotriphosphazene (Caminade et al. 2016a). Two types of fluorophores have been used for such purpose, both of them being derivatives of tyramine, i.e., maleimide (Fig. 8a) and julolidine (Fig. 8b). The maleimide derivative has been linked either off-center, or as terminal functions of several generations of phosphorhydrazone dendrimers (Franc et al. 2007). When linked off-center, it was synthesized up to the second generation, terminated by ammonium groups, for studying its interaction with DNA, in view of transfection experiments (Kazmierczak-Baranska et al. 2010). It was also synthesized up to the first generation terminated with azabisphosphonate functions, and used for detecting its interaction with monocytes, which are a pivotal cell population of innate immunity (Poupot et al. 2006). The julolidine derivative has been used only with first-generation dendrimers terminated with negatively charged entities, such as azabisphosphonate functions (Rolland et al. 2008), which was used for probing a specific inhibitory activity of this dendrimer towards CD4(+) T cell (Portevin et al. 2009). The julolidine was also used off-center for negatively charged first-generation dendrimers terminated by vinylcarboxylate (Ielasi et al. 2016) or azabiscarboxylate (Ledall et al. 2015), used in both cases in comparison with the azabisphosphonate terminal functions. Five dansyl derivatives were linked to a cyclotriphosphazene (Hameau et al. 2011), which was then grafted to another cyclotriphosphazene, finally functionalized by ammonium groups, to have water-soluble and highly fluorescent entities (Fuchs et al. 2008) (Fig. 8c). These compounds can be considered as Janus dendrimers, having two different faces (Caminade et al. 2012).
Fig. 8

Examples of fluorophores linked “off-center” to the core of dendrimers. a Maleimide derivative, with R corresponding to a second generation terminated with ammoniums or a first generation terminated with azabisphosphonates. b Julolidine derivative, with R corresponding to first generations terminated with either azabisphosphonates, azabiscarboxylates, or vinylcarboxylates. c Five dansyl derivatives, with R corresponding to first or second generation terminated with ammonium groups

Other examples of off-center dendrimers, and their use for grafting to materials

Another useful property of off-center dendrimers is the possibility to use this particular function for the grafting to materials. The first example with phosphorhydrazone dendrimers concerned a small dendrimer having two phosphonate groups for the grafting to a nanocrystalline mesoporous titania thin film, and five maleimide fluorophores (Fig. 9a). The titania film became highly fluorescent after the grafting of the dendrimers and was used as a sensitive sensor for the detection of hazardous phenols, in particular nitrophenols, which induced the quenching of the fluorescence (Martinez-Ferrero et al. 2008). A pyrene group was also grafted off-center, not for studying its fluorescence properties, but for inducing a non-covalent interaction with a graphene layer covering magnetic cobalt nanoparticles (Fig. 9b). The phosphine terminal functions were used for the complexation of palladium (Pd(OAc)2), then for catalyzing the coupling of ArBr with PhB(OH)2. This catalyzed reaction was carried out at 60 °C; at this temperature, the interaction between the graphene and the pyrene is suppressed, and the dendrimer carried out the catalysis in solution, but went back onto the graphene layer when cooling. Thus the dendrimer and the nanoparticles were recovered easily using a magnet and could be reused. In the case of the synthesis of felbinac (Ph-C6H4-CH2-CO2H), the process was carried out 12 times, with a quantitative yield at each run (Keller et al. 2013). The thioctic acid derivatives shown in Fig. 9c were used for the grafting to glass surfaces recovered by a thin layer of gold. The terminal functions were either ammonium or carboxylates, for ensuring the solubility in water. The surfaces covered by these dendrimers were used for the culture of human osteoblasts, which are cells that ensure the building of bones. Osteoblasts did not proliferate on the positively charged surface, and even underwent apoptosis; on the contrary, osteoblasts proliferated well on the negatively charged surface (de Jong et al. 2015). In a last example, a triethoxysilyl group was grafted off-center to a dendrimer having Boc-Tyramine as terminal functions (Fig. 9d) (Riegert et al. 2013). This dendrimer and other related dendrimers were used for the grafting to diverse types of nanoporous silica. After deprotection of the tyramine terminal functions, these compounds were used for trapping CO2 (Riegert et al. 2016).
Fig. 9

Different types of off-center functions for grafting to materials. a Phosphonates for TiO2. b Pyrene for non-covalent grafting to graphene. c Thioctic acid for gold. d Triethoxysilyl group for silica

Accelerated methods of synthesis of phosphorus dendrimers

The method of synthesis shown in Fig. 2 was also used in all the other cases shown in the previous paragraphs. This method is very robust and powerful, but it is a lengthy process, which necessitates two steps for each generation. Thus, it is important to try to shorten the synthetic process, in particular by obtaining a new generation at each step, and not every two steps. In these cases, layered dendrimers are obtained, in which the types of terminal groups are identical every two generations, and not every generation. These methods can be viewed also as a way to multiply more rapidly the number of terminal functions.

Phenol dialdehydes for accelerated syntheses of phosphorhydrazone dendrimers

The easiest way to multiply more rapidly the number of terminal functions consists in replacing 4-hydroxybenzaldehyde by hydroxydialdehydes. Two examples of such branched monomers are shown in Fig. 10. The first example concerned the 5-hydroxyisophthaldehyde (Fig. 10a), which was used in alternation with the phosphorhydrazide H2NNMeP(S)Cl2 as in Fig. 2, up to a dendrimer having 96 terminal functions, synthesized in only four steps (Servin et al. 2007). Very recently, a new hydroxydialdehyde based on trazine and piperazine was synthesized (Fig. 10b) to build dendrimers up to the fourth generation (96 terminal functions), also in only four steps. This new family of dendrimers presents unusual color and electrochemical properties, depending on the step considered. It was possible for the first time, for a dendrimer having no “traditional” electroactive entities, to monitor the growing of the dendrimer by electrochemistry (Dib et al. 2016). Comparison of the number of terminal functions at each step, using either 4-hydroxybenzaldehyde or the hydroxydialdehydes, demonstrates the usefulness of this method to multiply more rapidly the number of terminal functions (Fig. 10c).
Fig. 10

a, b Two examples of phenol dialdehydes used for accelerated synthesis of phosphorhydrazone dendrimers. c Comparison of the number of terminal functions at each step, using either 4-hydroxybenzaldehyde as shown in Fig. 2b, or the hydroxydialdehydes (a, b)

Other accelerated methods of synthesis, based on P=N–P=S linkages

The Staudinger reaction between phosphines and azides, which creates P=N linkages, is a useful method of synthesis of primary amines, due to the easy hydrolysis of this linkage. However, using a thiophosphorylazide instead of a simple organic azide strengthens the stability of the P=N bond, due to an electronic delocalization all along the P=N–P=S linkage (Furer et al. 2015b). We have demonstrated a long time ago the usefulness of these linkages for the straightforward synthesis of original cryptands and spherands (Mitjaville et al. 1994), and also for the synthesis of dendrimers in three steps for each generation, up to the third generation (Galliot et al. 1995), or two steps up to the fourth generation (Sebastian et al. 2000). However, we have mainly used the Staudinger reaction for accelerated methods of synthesis of dendrimers, using two branched monomers, and combining Staudinger reactions between phosphines (B) and azides (C), and condensation reactions between hydrazides (A) and aldehydes (D) (Fig. 11). The first example concerned the reaction of AB 2 and CD 2 monomers. The reaction was carried out up to the fourth generation in only four steps (Fig. 11a). As both reactions are quantitative, and the only by-products are N2 and H2O, the same process was carried out one-pot, by adding sequentially the stoichiometric quantities of reagents, without isolation up to the fourth generation, for which the purity was equivalent to the purity of the same generation isolated at each step (Brauge et al. 2001b), (Brauge et al. 2001c). Another process used a different combination of the same functions, starting from monomers CA 2 and DB 2 . In this case also, the synthesis was carried out up to the fourth generation in four quantitative steps (Fig. 11b) (Maraval et al. 2003b). An analogous concept has been developed using AB 5 and CD 5 monomers, obtained thanks to the specific reactivity of one chlorine of N3P3Cl6. In only three steps, a dendrimer of the third generation, possessing 750 phosphines as terminal functions has been obtained (Fig. 11c). The crowding is very high in this dendrimer, and 4 days at 100 °C were needed to go to completion in the third step. This condensation step is generally carried out at room temperature in a few hours for more classical dendrimers. Of course, combination between AB 2 and CD 5 , or AB 5 and CD 2 monomers is possible and was studied (Maraval et al. 2003a).
Fig. 11

Accelerated methods of synthesis of dendrimers incorporating P=N–P=S or P=N–P=N linkages in their structure. a Using AB 2 and CD 2 monomers. b Using CA 2 and DB 2 monomers. c Using AB 5 and CD 5 monomers

Instead of using two monomers, we have also synthesized phosphorus dendrimers using a single branched monomer of type CB 2 , in which both phosphines (B) are protected by BH3. Both dendrimers and hyperbranched polymers were synthesized from this monomer. The hyperbranched polymers were synthesized one step, by adding an amine such as DABCO (1,4-diazabicyclo[2.2.2.]octane) or NEt3 to deprotect the phosphines. The dendrimers were synthesized step-by-step, applying first the Staudinger reaction of the azide with phosphine terminal functions, then the deprotection of the protected terminal phosphines. The synthesis of these dendrimers was carried out up the fifth generation, as shown in Fig. 12. It must be emphasized that despite their easy synthesis, the hyperbranched polymers have very different properties compared to the dendrimers built with the same monomer. Indeed, the polydispersity of the hyperbranched polymers is 8.1 for a weight comparable to that of the G4 dendrimer, for which the polydispersity is 1.012 (Merino et al. 2001).
Fig. 12

Protected CB 2 monomer used for the one step synthesis of hyperbranched polymers (right) and for the step-by-step synthesis of dendrimers (left), both including P=N–P=S linkages at all layers

In all these cases, there are phosphines as terminal functions at some steps, which can be very useful for complexing diverse metals (Caminade et al. 1998) and for catalysis (Caminade et al. 2008, 2016b). There are also P=N–P=S linkages everywhere in the internal structure, which have a versatile reactivity that will be displayed in the forthcoming paragraphs.

P=N–P=S linkages at the core of dendrons for the synthesis of special dendritic architectures

The P=N–P=S linkages obtained from the reaction of vinyldiphenylphosphine with the monomer CD 2 are particularly interesting because this linkage induces an activation of the vinyl group (Furer et al. 2015b). It can react in Michael-type additions with diverse functionalized amines. Figure 13a displays the example of the addition of ethylene diamine, used in large excess, to an activated vinyl group at the core of a dendron having dimethyl amine as terminal functions. The resulting primary amine at the core of the dendron was then used to react in a second Michael-type addition with the vinyl group of another dendron, having nitrile terminal functions, to afford a Janus dendrimer schematized in Fig. 13b. Diverse types of non-symmetrical dendritic structures have been obtained in this way, as schematized in Fig. 13c (Maraval et al. 2000a). The same type of addition has been carried out with cyclam, covering the surface of nanolatexes (diameter 15 nm), and dendrons having Girard T reagents as terminal functions (Fig. 13d). The number of dendrons grafted to the nanolatexes depends on the size of the dendron, affording an average value of 600–800 positive charges per nanoparticle. Remarkably, the colloidal stability of the nanolatexes in water was greatly improved by the grafting of the dendrons, as well as the thermal stability (Larpent et al. 2004). Furthermore, these functionalized nanolatexes form hydrogels in water, as was previously observed with dendrimers having the same terminal functions (Marmillon et al. 2001). Another example of the utility of these activated vinyl groups concerns Janus dendrimers having on one side carboxylate groups and on the other side tertiary amine groups (Fig. 13e) (Maraval et al. 2006). These compounds were used for the layer-by-layer deposit onto positively charged silica surface, by electrostatic interactions. After deposit of the first layer, methyliodide was added to alkylate the tertiary amines, affording a positively charged surface to which a second layer of the same Janus dendrimer was deposited (Lee et al. 2016). This is an original way to build multilayers, which were previously obtained using negatively and positively charged dendrimers (Kim et al. 2005; Feng et al. 2008; Lazzara et al. 2010; Knoll et al. 2011).
Fig. 13

Examples of special dendritic structures obtained by reactions of the activated vinyl group at the core of dendrons. a Addition of ethylene diamine, followed by a second Michael-type addition to another dendron, to afford a Janus dendrimer. b Schematized Janus dendrimer obtained in a. c Schematization of diverse types of special dendritic structures. d Michael addition of a water-soluble dendron to cyclam on the surface of a nanolatex. e Structure of another Janus dendrimer negatively charged on one side, with tertiary amines on the other side

Reactivity of the internal P=N–P=S linkages: towards dendrons inside dendrimers

The electronic delocalization all along the P=N–P=S linkages induces a mesomeric form with a negative charge on sulfur and a positive charge on phosphorus (+P–N=P–S). It means that the sulfur atom can potentially react with electron-deficient entities (metallic derivatives or organic electrophiles). To observe more easily the reactivity of the P=N–P=S linkages, we have generally introduced them at a single layer inside the dendrimers, and not at several or all layers as shown in Figs. 11 and 12, using the method of synthesis shown in Fig. 2 for the layers not including such linkages.

Specific alkylation or complexation on the sulfur atom of the P=N–P=S linkages

The sulfur atoms included in P=N–P=S linkages behave differently than all the other P=S groups of the dendrimers. Indeed, the softness and electrophilicity of the sulfur atom of the P=N–P=S linkages are higher than for the other P=S groups, and this increased electron density allows for instance the regiospecific complexation of gold (Furer et al. 2015a). The P=N–P=S linkages have been included at different layers inside different types of phosphorus dendrimers, as illustrated in Fig. 13. The first cases concerned dendrimers having two P=N–P=S linkages at the core, linked by a C6 alkyl chain (Fig. 14a) and six P=N–P=S linkages emanating from a cyclotriphosphazene core (Fig. 14b) (Larre et al. 1998c). Recently, the same concept has been developed for the synthesis of “onion peel” dendrimers, i.e., dendrimers having different chemical entities at each layer. In this case, 24 P=N–P=S linkages were complexed at the level of the second generation of a third generation onion peel dendrimer. None of the other P=S groups included in this dendrimer were complexed (Fig. 14c) (Katir et al. 2015).
Fig. 14

Examples of regiospecific complexation of gold on P=N–P=S linkages. a Constituting the core. b Linked to the core. c Placed at the second generation of “onion peel” dendrimers

The higher electron density on sulfur atoms included in P=N–P=S linkages also induces a specific reactivity with organic electrophiles. First attempts were carried out with methyltriflate, on dendrimers built from two P=N–P=S linkages at the core linked by a C6 alkyl chain. These dendrimers were built up to the seventh generation, having 2 P=N–P=S at the core, 64 P=N–P=S at the level of the fourth generation, and 256 P=N–P=S at the level of the sixth generation. Only the layers having the P=N–P=S linkages could be alkylated. This was in particular demonstrated by dramatic changes in the 31P NMR spectra of the fifth generation (two levels of P=N–P=S linkages, at generations 0 and 4) (Fig. 15a). Indeed, the signals corresponding to the P=N–P=S linkages are two doublets in all cases, but with very different chemical shifts and coupling constants: 20.4 and 51.2 (2JPP0 = 34 Hz) and 14.2 and 51.3 (2JPP4 = 34 Hz) before alkylation for the fifth generation, and 27.9 and 19.6 (2JPP0 = 18.5 Hz) and 21.9 and 23.8 (2JPP4 = 17.5 Hz) after alkylation, respectively (Larre et al. 1997). Alkylation reactions with other triflates such as allyl and propargyl triflates have been carried out on other members of the same family of dendrimers (Fig. 15b) (Larre et al. 1998b). Alkylation reactions have been carried out also with dendrimers built from the cyclotriphosphazene core and terminated with non-reactive phenyl groups (Fig. 15c) (Larre et al. 1998a).
Fig. 15

Reactivity of the P=N–P=S linkages inside dendrimers. a Alkylation on sulfur. b Alkylation on sulfur, desulfurization, and Staudinger reaction. c Alkylation on sulfur, desulfurization, alkylation on phosphorus, and Staudinger reaction with various azides. d Grafting of fluorescent groups via Staudinger reaction

The alkylation of sulfur induces a weakening of the strength of the PS bond, which can be easily cleaved using a nucleophilic phosphine such as P(NMe2)3, to generate tricoordinated phosphorus atoms inside the structure (Fig. 15b, c). The PIII inside the structure can be alkylated using alkyliodides, such as methyliodide and allyliodide (Fig. 15c), but can react also with diverse azides in Staudinger reactions (Fig. 15b, c). The reaction with N3-P(S)(OC6H4-CHO)2 (called monomer CD 2 in Fig. 11) is particularly interesting, as will be seen in the forthcoming paragraphs (Fig. 15c) (Larre et al. 1998a). All the process is also compatible with the presence of aldehyde terminal functions (Fig. 15d). It has been used in particular for the grafting of fluorescent pyrene groups inside the dendrimers, using the Staudinger reaction in the last step. These fluorescent functions revealed that the internal structure contains many molecules of solvents, as the movement of the internal pyrene groups was analogous to the movement of pyrenes in a small model compound. Indeed, the ratio of the intensity of pyrene-pyrene excimer and of pyrene depended only on the solvent used and not on the size of the molecules tested (monomer or dendrimer) (Fig. 15d) (Brauge et al. 2001a).

Reactivity of aldehyde internal functions

The reaction of the azidodialdehyde shown in Fig. 15c inside the structure of dendrimers generates P=N–P=N–P=S linkages, and two aldehydes, from which a versatile reactivity via condensation reactions, very unique among all types of dendrimers, have been displayed (Fig. 16). Condensation reactions have been carried out with 1-azido-3-aminopropane, affording 12 azides inside the structure, and with 4′-aminobenzo-15-crown-5, affording 12 crown-ethers inside the structure (Larre et al. 1998a). Another condensation reaction was carried out with methylhydrazine, affording NH internal functions, on which Ph2PCH2OH was condensed. This special dendritic structure possesses two different sites for the complexation of gold: the sulfur atom of the P=N–P=N–P=S linkages and the internal phosphines; both were indeed complexed by gold (Fig. 16) (Larre et al. 1998c).
Fig. 16

Examples of reactivity inside dendrimers, starting from internal aldehydes

Introducing new branches inside the structure of dendrimers

Besides the reactivity shown in Fig. 16, the aldehyde internal functions were used also for growing new dendritic branches inside the dendrimer. Two methods were applied, either the classical two-step process shown in Fig. 2, or the three-step process shown in Fig. 17a, which creates P=N–P=S linkages at each generation. This dendrimer is constituted of two different series of branches, located in precise areas, as shown by the full structure of the largest dendritic compound shown in Fig. 17b. This compound is certainly the most original type of dendritic compound ever synthesized (Galliot et al. 1997). The presence of P=N–P=N–P=S and P=N–P=S linkages in this compound was used for the specific complexation of Au-Cl on the sulfur atoms of these linkages (Larre et al. 1998c). The step-by-step synthesis resulted in the synthesis of generation 4 branches inside the main dendrimer. However, attempts to graft directly dendrons of third generation inside the dendrimer failed; only the second-generation dendron could be grafted on the internal aldehydes (Maraval et al. 2000b). The internal aldehyde of the second generation was used for the formal [3 + 2] cycloaddition of 2-phosphino-1-zirconaindene, which led to stable anionic zwitterionic zirconocene complexes inside the structure (Cadierno et al. 1999).
Fig. 17

a Synthesis of new branches inside a main dendrimer. b Full structure of the largest dendritic entity

Viologen-containing phosphorus dendrimers

Important properties of dendrimers concern their use for biological experiments. For this purpose, it is highly desirable to have water-soluble compounds. In the case of dendrimers, this is generally achieved by introducing charges on the surface of the dendrimers, in particular for dendrimers having a rather hydrophobic interior, as the phosphorhydrazone dendrimers. Introducing charges inside the structure of the dendrimers and not on the surface should totally modify the properties. For this purpose, viologen units (dialkylated 4,4′-bipyridine) were first introduced in the structure of small phosphorus dendrimers (generations 0 and 1) (Katir et al. 2012), then also in the structure of mixed carbosilane and phosphorus dendrimers (up to generation 2) (Moreno et al. 2015). All of these dendrimers were built either from the trifunctional S=P(NMeNH2)3 or hexafunctional P3N3(NMeNH2)6 core (Galliot et al. 1993), condensed with 3 or 6 equivalents, respectively, of viologen entities functionalized with a benzaldehyde. In all cases, the counter ions can be modified; examples with PF6, Br and Cl are shown in Fig. 18.
Fig. 18

Examples of dendrimers incorporating viologen units in their structure

Different types of biological experiments were carried out with these new viologen derivatives. The main conclusion was that the biological behavior strongly depends on the size, molecular weight, number of viologen units, and nature of the terminal functions, as an illustration of the CNDP concept. In a first paper, hemolysis, cytotoxicity, antibacterial, and antifungal activity induced by these phosphorus-viologen dendrimers were investigated. The most hemolytic dendrimers, measured on red blood cells obtained from healthy donors, were those of first generations, whereas generation 0 ended by PEG (polyethyleneglycol) was the least hemolytic. The cytotoxicity, measured with B14 Chinese hamster peritoneal fibroblasts, indicated also that the least toxic was the generation 0 ended by PEGs. Interestingly, cytotoxicity measured with N2a mouse neuroblastoma cell lines showed that this PEG dendrimer was the most toxic. A dendrimer which is harmless to normal cells but highly toxic to cancer cells is particularly interesting. The anti-microbial activity was tested on a Gram-positive bacterium, three Gram-negative bacteria, and yeast. In general, the dendrimers having the largest number of viologen units have the highest anti-microbial activity, whereas the PEG dendrimer has no activity (Ciepluch et al. 2012a). The influence of viologen-based dendrimers on human serum albumin (HSA), which is the most abundant protein in plasma, has been also investigated. All viologen dendrimers decreased significantly the HSA fluorescence intensity, but they do not modify the circular dichroism (CD) spectra of albumin, except for those having aldehyde terminal functions (Ciepluch et al. 2012b). The cytotoxicity and the interaction with HSA were also studied with the mixed phosphorus-viologen-carbosilane dendrimers, but it was shown that in this case, the properties mainly depended on the ammonium surface groups, and not on the internal structure (Moreno et al. 2015). The interaction of these mixed dendrimers with several proteins (alkaline phosphatase from E. coli, human aspartate transaminase and l-lactate dehydrogenase from rabbit muscles) was also studied (Szwed et al. 2016).

Several experiments were carried out with the viologen dendrimers in the context of neurodegenerative diseases. The toxicity of the generation 0 viologen dendrimers having phosphonate terminal functions, built from either the trifunctional or the hexafunctional core, was tested towards embryonic mouse hippocampal cells (cells from the central nervous system). The cytotoxicity of these dendrimers was low in both cases, and they declined the level of reactive oxygen species (ROS), due to their ability to quench ROS (Lazniewska et al. 2013). Furthermore, these dendrimers can prevent damages induced by rotenone (a pesticide) on these cells (Milowska et al. 2014). The inhibition by several viologen dendrimers of acetylcholinesterase and butyrylcholinesterase activity, two enzymes that are deeply implicated in neurodegenerative diseases, was also demonstrated (Ciepluch et al. 2013). The inhibition of α-synuclein fibril formation by the same series of viologen dendrimers was more pronounced when using the phosphonate derivative, compared to the PEG derivative, showing a potential therapeutic strategy in Parkinson’s disease and in other synucleinopathies (Milowska et al. 2013).

Influence of internal modifications on the biological properties of dendrimers

The first-generation phosphorhydrazone dendrimer having azabisphosphonate terminal functions (Fig. 19a) has many biological properties towards the human immune system. Indeed, several white blood cells (mononuclear cells) are triggered by this dendrimer. The first interaction was observed with monocytes, in which the dendrimer penetrates very rapidly (1 min) (Poupot et al. 2006), and specifically (Ledall et al. 2015), and which were activated through an anti-inflammatory pathway (Fruchon et al. 2009). The second interaction detected was with Natural Killer cells (NK), which are multiplied by several hundred (Griffe et al. 2007). The complex interactions between these two types of immune cells were recently elucidated (Poupot et al. 2016). The third interaction concerned the regulatory activity of this dendrimer towards T CD4+ lymphocytes (Portevin et al. 2009). This dendrimer was also shown efficient in vivo, for mice which suffered from either a rheumatoid arthritis-like disease (Hayder et al. 2011) or from a multiple sclerosis-like disease (Hayder et al. 2015), and it was shown non-toxic for non-human primates (Fruchon et al. 2015).
Fig. 19

Identical terminal functions, but different internal structures. ac Different types of phosphorhydrazone dendrimers. d Thiophosphate dendrimer. e Carbosilane dendrimer. f PPI dendrimer. g PAMAM dendrimer. h Polylysine dendrimer

In view of all these important properties, a large screening to determine the structure/activity relationship was carried out. In first attempts, the nature of the terminal functions (Griffe et al. 2007), the generation, and the number of terminal functions (Rolland et al. 2008) were studied. It was deduced from these experiments that 8 to 12 symmetrical azabisphosphonate linkages are necessary to observe the biological properties. Thus, in a next step of structural modifications, we decided to modify the internal structure of dendrimers, while keeping the same type and number of azabisphosphonate groups on the surface. For this purpose, we synthesized other types of phosphorhydrazone dendrimers, one with longer internal branches (Fig. 19b), and one with longer linker to the azabisphosphonates (Fig. 19c). We also synthesized other “inorganic” dendrimers, one based on thiophosphate linkages (Fig. 19d) (Salamonczyk et al. 2000), and one based on carbosilane branches (Fig. 19e) (Zhou and Roovers 1993), both having also azabisphosphonate terminal groups. Finally, we synthesized “organic” dendrimers, based on nitrogen at the branching points, of types PAMAM (Fig. 19f) (Tomalia et al. 1985), PPI (Fig. 19g) (de Brabander van den Berg and Meijer 1993), and poly(l-lysine) (Fig. 19h) (Aharoni et al. 1982), all of them having azabisphosphonate terminal groups. The ability of all these families of dendrimers to activate monocytes was checked. To our surprise, despite the presence of the same type of terminal functions and of an analogous number of these terminal functions, all the dendrimers with nitrogen at the branching points (Fig. 19f–h) have absolutely no activity, whereas all the others are active, the most active being still the first dendrimer synthesized, shown in Fig. 19a. To try to understand this astonishing result, theoretical studies by molecular modeling were carried out with all the dendrimers shown in Fig. 19, in explicit water. These studies showed that these very different dendrimers can be separated into two families: those having a directional structure in water, with all the terminal functions gathered on the same side, which were active, and those having the terminal functions spread all over the surface, which were non-active. This was the very first example of the influence of the internal structure of dendrimers on their properties, carried out with a large number of families of dendrimers (Caminade et al. 2015).

Conclusion

In this review, we have shown how modifications of the internal structure of phosphorhydrazone dendrimers, at the level of the architecture and of the chemical composition, can deeply modify the properties of dendrimers. Phosphorus-containing dendrimers are certainly one of the most versatile class of dendrimers, due to the large number of modifications offered by phosphorus chemistry. Among the examples given, one can cite the incorporation of ferrocenes inside the structure, to modify the electrochemical properties, leading to the very first example of a switch ON-OFF dendritic catalyst, and the incorporation of fluorescent entities at different level, for imaging biological events at the cellular level, or imaging blood vessels of living animals. Incorporation of charges inside the structure (in particular viologen units) for studying their biological properties has been also shown. Different methods for accelerating the synthesis of dendrimers have been displayed (only one reaction per generation), affording layered dendrimers. Of interest are those incorporating P=N–P=S linkages in their structure, which display an original reactivity on the sulfur atom, which has led to the synthesis of particularly original dendritic architectures. Finally, the comparison of the anti-inflammation properties of a series of dendrimers having the same type and number of terminal functions, but a different internal architecture and chemical composition, has demonstrated the dramatic influence of these parameters on the biological properties. Undoubtedly, the CNDPs are of paramount importance for defining and classifying the different types of dendrimers and dendritic structures.

Notes

Acknowledgements

Thanks are due to the CNRS (Centre National de la Recherche Scientifique) for financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.CNRS, LCC (Laboratoire de Chimie de Coordination)Toulouse Cedex 4France
  2. 2.LCC-CNRS, Université de Toulouse, CNRSToulouseFrance

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