Original Multivalent Copper(II)-Conjugated Phosphorus Dendrimers

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Original Multivalent Copper(II)-Conjugated Phosphorus Dendrimers and Corresponding Mononuclear Copper(II) Complexes with Antitumoral Activities Nabil El Brahmi,†,§,⊥ Saïd El Kazzouli,† Serge M. Mignani,*,‡ El Mokhtar Essassi,§ Geneviève Aubert,∥ Régis Laurent,⊥ Anne-Marie Caminade,⊥ Mosto M. Bousmina,#,∇ Thierry Cresteil,∥ and Jean-Pierre Majoral*,⊥ †

Institute of Nanomaterials & Nanotechnology (INANOTECH), Moroccan Advanced Science, Innovation and Research (MAScIR) Foundation, Avenue de l’Armée Royale, Madinat El Irfane, 10100, Rabat, Morocco ‡ Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, 45, rue des Saints Pères, 75006 Paris, France § Laboratoire de Chimie Organique Hétérocyclique, Pôle de Compétences Pharmacochimie, Université Mohammed V-Agdal, BP 1014 Avenue Ibn Batout, Rabat, Morocco ∥ ICSN-CNRS UPR 2301, Avenue de la Terrasse, 91198 Gif sur Yvette, France ⊥ Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France # Hassan II Academy of Sciences and Technology, Avenue Mohammed VI, km4, 10222 Rabat, Morocco S Supporting Information *

has increased in modern times with about 25 million people suffering from this deadly and devastating disease worldwide.2 Current cytotoxic cancer chemotherapies often have a poor therapeutic index and are associated with side effects which can strongly vary depending on the cancer type, the treatment, and the person. The application of nanotechnology for cancer therapy has strongly received attention in recent years and represents a new interesting approach for cancer treatment offering new potential solutions to tackle cancer progression and metastasis.3 Due to their high degree of molecular uniformity, with perfect control of their size, shape, and surface chemistry, dendrimers as carriers offer various drug-design opportunities and important suitable alternative approaches to the delivery of biologically active compounds for instance in oncology. Metal complexes, as anticancer therapeutic agents, are generally either “classical” Pt(II)-based clinical drug complexes such as cisplatin, carboplatin, oxaliplatin, and so forth, or “nonclassical” metal complexes such as, for instance, titanocene-based complexes, ferroquine, and platinum (DACH)Pt-malonato-Tam complex derivatives.3 In addition to the historical Pt(II) and Pt(IV) chemotherapeutics,4 currently, other main essential metal-based antitumor drugs have been emphasized involving iron, cobalt, manganese, or copper.5 Up to date, very few examples have been pointed out on the preparation of dendrimer conjugated-metallodrugs improving the pharmacological profile as the pharmacokinetic (PK) and pharmacodynamic (PD) behaviors of the native metallodrugs. Indeed, both dendrimer-drug encapsulated or conjugated have

ABSTRACT: Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation Gn (n = 1 to 3): N-(pyridin-2-ylmethylene)ethanamine for dendrimers 1Gn, N-(di(pyridin-2-yl)methylene)ethanamine for dendrimers 2Gn, and 2-(2-methylenehydrazinyl)pyridine for dendrimers 3Gn. The results indicated that the most potent derivatives are 1Gn and 1Gn-Cu versus 2Gn, 2Gn-Cu, and 3Gn, 3Gn-Cu. A direct relationship between the growth inhibitory effect and the number of terminal moieties or the amount of copper complexed to the dendrimer was observed in copper-complexed 1 series and noncomplexed 1 series. These data clearly suggested that cytotoxicity increased with the number of terminal moieties available and was boosted by the presence of complexed Cu atoms. Importantly, no cytotoxic effect was observed with CuCl2 at the same concentrations. Finally, 1G3 and 1G3-Cu have been selected for antiproliferative studies against a panel of tumor cell lines: 1G3 and 1G3-Cu demonstrated potent antiproliferative activities with IC50 values ranging 0.3−1.6 μM. Interestingly, the complexation of the terminal ligands of 1G3 dendrimers by copper(II) metal strongly increased the IC50 values in noncancer cells lines referred to as “safety” cell lines. KEYWORDS: dendrimers, copper complexes, phosphorus, antiproliferative properties, nanomedicine

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t is generally admitted that cancer is of universal public health concern causing annually about 13% of all human deaths.1 Despite important progresses in several cancer therapies including chemotherapy, radiation therapy, and surgery, cancer © 2013 American Chemical Society

Received: Revised: Accepted: Published: 1459

January 12, 2013 February 12, 2013 February 14, 2013 February 14, 2013 dx.doi.org/10.1021/mp4000184 | Mol. Pharmaceutics 2013, 10, 1459−1464

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been developed demonstrating the strong potential of dendrimers in medicine as novel nonviral gene delivery nanocarriers.6 Several dendrimers are currently commercially available.7 Interestingly, Starpharma (Melbourne, Australia) started two pivotal phase III clinical trials for the treatment of bacterial vaginosis with Vivagel.8 This anionic G4-poly (L-lysine)-type dendrimer has 32 naphthalene disulfonate groups on the surface and showed potent topical vaginal microbicide activity. In addition, the use of biologically active dendrimer per se has been also emphasized.9 In this direction, a powerful approach has been illustrated by a phosphorus dendrimer of generation 1 decorated with 12 azabisphosphonic terminal groupswith cyclotriphosphazene as the coreshowing, outstandingly, high in vivo anti-inflammatory activity useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis. After only 6 weekly injections of 10 mg/kg of phosphorus dendrimer, the inflammation was completely inhibited in two types of mouse model with a decrease in paw swelling and arthritis histopathology with ankle joints completely normal and intact cartilage. Based on our first analysis, no particular toxicity effects were observed.10 Our goal was to design biocompatible phosphorus multivalent dendrimers bearing a cyclotriphosphazene core,11 as the scaffold for the synthesis of original multivalent dendrimers complexing metals like copper(II) as well as to prepare their corresponding mononuclear copper(II) complexes as depicted in Scheme 1. As shown in Table 1 and Scheme 2, several generations (Gn) of dendrimers have been synthetized (Gn = 1, 2, and 3) bearing three different host−guest complexation chelators as terminal groups. Thus, a total of three ligands 4−6 and their corresponding mononuclear copper(II) complexes 4-Cu, 5-Cu, and 6-Cu, and sixteen novel dendrimers G1−G3 and G1−Cu−G3−Cu were prepared. In the present study, we examined the antiproliferative effects of ligands 4−6 and their corresponding mononuclear copper(II) complexes 4-Cu, 5-Cu, and 6-Cu, and plain dendrimers as well as Cu(II)-complexed dendrimers against solid and liquid tumor cell lines. Finally, based on these results, a preliminary structure− activity relationship was established between cell growth inhibition against several solid and liquid tumor cancer cell lines and the structure and composition of dendrimers. Our attention has been directed toward copper at least for three main reasons: (1) nowadays several families of copper complexes have been studied (in vitro and few in vivo experiments) as potential antitumor agents (e.g., thiosemicarbazone complexes, conjugate Schiff base complexes, etc.); (2) their mode of action is different than that of cisplatin (e.g., covalent binding to DNA); (3) these complexes might be able to overcome inherent/ acquired resistance to cisplatin.12 To the best of our knowledge, only one recent example concerns a (G0) poly(amidoamine) (PAMAM) heptanuclear copper(II) metallodendrimer which presents a strong in vitro cytotoxicity against leukemia (MOLT-4) and breast cancer MCF-7 cell lines.13 As shown in Scheme 2, the selected copper ligands are N(pyridin-2-ylmethylene) ethanamine for dendrimers 1Gn (n = 1−3), N-(di(pyridin-2-yl)methylene)ethanamine for dendrimers 2Gn (n = 1 and 3) and 2-(2-methylenehydrazinyl)pyridine for dendrimers 3Gn (n = 1−3). The number of terminal groups on the surface of the dendrimer is 12, 24, and 48 for dendrimers of generation 1, 2, and 3, respectively (Table 1). The copper(II) chelator moiety 1 has been previously described by Zhao et al.13 in a (G0) poly(amidoamine) (PAMAM) dendritic

Scheme 1. Structure of the Ligands 4-6 and of Their Corresponding Mononuclear Copper(II) Complexes 4-Cu, 5-Cu, and 6-Cu

Schiff base complex and by Govender and co-workers in DABPOPAM series complexing ruthenium metal.14 Dendrimer synthesis was accomplished by a straightforward synthetic pathway emphasized in Scheme 2 (see Supporting Information). The respective role of three factors, for example, the structural feature of the three coordination ligands, the dendrimer generation (Gn), and the presence or not of copper(II) on the surface was explored through the expected cytotoxic activities on human cell lines. First, based on an MTS assay,15 we examined the in vitro antiproliferative effects of the eight dendrimers (1G1−1G3, 2G1, 2G3, 3G1−G3) and their corresponding Cu complexes (1G1− Cu−1G3−Cu, 2G1−Cu, 2G3−Cu, 3G1−Cu−3G3−Cu) on both solid tumor KB (epidermal carcinoma) and leukemia HL60 (promyelocytic) cells. These cell lines are representative markers for anticancer activity. The behavior of the corresponding monomers 4−6 and their Cu complexes 4-Cu, 5-Cu, and 6-Cu featuring the surface shell of the dendrimers (Scheme 1) was also investigated to compare their activity to that of the dendrimers. In a first approach, we compared dendrimers 1G [bearing as terminal moiety the N-(pyridin-2-ylmethylene)ethanamine motif], 2G [N-(di(pyridin-2-yl)methylene)ethanamine], and 3G [2-(2-methylenehydrazinyl)pyridine] to evaluate the contribution of the copper-guest chelator moiety alone on the cellular growth. In the absence of Cu(II), dendrimers 3G did not have any inhibitory effect on cell proliferation (≤7% at 10 μM), whatever the generation (Gn) (e.g., number of terminal moieties), indicating that the 2-(2-methylenehydrazinyl)pyridine motif is not toxic by itself for cells. Conversely, dendrimers 1G and 2G display a potent antiproliferative activity at 10 μM, but this effect severely declines at 1 μM. Then the impact of the terminal moieties number on the antiproliferative activity was examined: no substantial effect was noticeable at 10 and 1 μM for dendrimer 1G, whereas dendrimer 2G3 is unexpectedly less active than 2G1 at the concentration 1 μM. Finally, the role of Cu(II) was determined by comparing the inhibition of cell growth in the presence of dendrimers bearing terminal moieties complexed or not with Cu(II). With dendrimers 3G, devoided of basic activity, the addition of Cu(II) dramatically reduces the cellular proliferation at 10 μM (≥70%) but has no effect at 1 μM. With the active dendrimers 1G and 2G, no additional augmentation was observed at 10 μM. A marginal increase due to the presence of Cu(II) was noticed at 1 μM with dendrimers 2G while in the 1G series, the complexation of dendrimers with Cu(II) was associated with the augmentation of 1460

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Table 1. Multivalent Phosphorus Dendrimers and Corresponding Multivalent Copper-Conjugated Phosphorus Dendrimers Prepared

dendrimer toxicity and was related to the generation number in both cell lines. Thus, as displayed in Figure 1, a direct relationship between the growth inhibitory effect (% inhibition at 1 μM against HL60 cell line) and the number of the terminal moieties and/or the amount of copper complexed with the dendrimer (μg/L) was observed in the copper-complexed 1 series versus the noncomplexed 1 series including monomers. Importantly, the monomers 4 and 5 displayed, per se, very low inhibition at 1 μM ranging 0−4% against both KB and HL60 cell lines, whereas inhibition by 6 did not exceed 13% at 1 μM. A similar effect was obtained with the corresponding Cu(II)based monomers 4-Cu, 5-Cu, and 6-Cu. Furthermore, CuCl2 alone is ineffective to prevent cell proliferation at 10 and 1 μM. Lastly, when cells are exposed to the noncomplexed dendrimer 1G3 alone or to the mixture of noncomplexed dendrimer 1G3 and CuCl2, no additive effect can be observed at 10 or 1 μM (data not shown). This result underlines the crucial role for antiproliferative potency of the complexation of copper(II) with diamino-chelator moieties on the surface of phosphorus dendrimers. Therefore it is possible to conclude that the nature and number of the terminal moiety play a major role in the antiproliferative potency of dendrimers and that the complexation of dendrimers with Cu(II) boosts this effect. To illustrate these conclusions, antiproliferative activity of couples of dendrimers of generation 3, 1G3 and 1G3−Cu, 2G3 and 2G3−Cu, and 3G3 and 3G3−Cu on KB (A) and HL60 (B) cells has been compared in Figure 2. A 72 h treatment of KB and HL60 cell lines with dendrimers at a concentration of 10 μM resulted in a reduction >50% of cell proliferation with dendrimers 1G3, 1G3−Cu, 2G3, 2G3−Cu, and 3G3−Cu. Only 1G3−Cu displayed a very potent antiproliferative activity (>80%) at both 10 μM and 1 μM against KB and HL60 cell lines. To go further, we selected the couple of dendrimers 1G3 and 1G3−Cu for additional investigations on inhibitory effects upon a panel of cancer cell lines including HCT116 (human colon cancer), MCF7 (hormone-responsive breast cancer), OVCAR8

Figure 1. Growth inhibitory effects (expressed as the percentage of growth inhibition at 1 μM ± SE for two experiments performed in triplicate) of 4-Cu, 4 and 1Gn−Cu- and 1Gn against the HL60 cell line. Gn = generation of the dendrimer corresponding to the number of terminal groups on the surface of the dendrimer: 0: monomer (29 μg Cu/L); G1: 12 (348 μg Cu/L); G2: 24 (696 μg Cu/L); G3: 48 (1392 μg Cu/L), i.e., 1 Cu per terminal ligand.

(ovarian carcinoma), and U87 (human glioblastoma-astrocytoma, epithelial-like) and two noncancer cell lines, namely, MCR5 (proliferative human lung fibroblasts) and the quiescent EPC (endothelial progenitor cells, Cyprinus carpio). Concentrations of 1G3 and 1G3−Cu causing a half-maximum inhibition of cell proliferation (IC50) were calculated: these evaluations on “normal” dividing and nondividing cells are believed to figure a “safety ratio” and might suggest that these chemicals are specifically acting on cells with a rapid proliferation, for example, cancer cells. Data shown in Figure 3 confirmed the potent antiproliferative inhibition of the copper(II)-complexed dendrimer 1G3−Cu vs the plain dendrimer 1G3 against KB and HL60 cell lines (∼2−4 fold improvement). The dendrimers 1G3 and 1G3−Cu displayed similar potency against HCT116, MCF7, and U87 cancer cell 1461



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Scheme 2. General Structure of Multivalent Phosphorus Dendrimers and Corresponding Multivalent Copper-Conjugated Phosphorus Dendrimers

Interestingly, complexation of 1G3 with Cu(II) considerably increased its IC50 values in the noncancer cells lines EPC and MRC5: the ratio IC50 1G3−Cu/IC50 1G3 is respectively 4 and

lines, showing no strict copper(II) requirement. 1G3 is about 2-fold more potent than the corresponding 1G3−Cu against OVCAR8 cell line. 1462



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ASSOCIATED CONTENT

S Supporting Information *

Syntheses of dendrimers 1G1−1G3, 2G1, 2G3, and 3G1−3G3 and of the corresponding Cu complexes 1G1−Cu−1G3−Cu, 2G1− Cu, 2G3−Cu, and 3G1−Cu−3G3−Cu, (31P, 1H, 13C) NMR and IR data. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (S. Mignani); [email protected] ( J.-P. Majoral). Present Address ∇

Euro-Mediterranean University of Fez, Morocco.

Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 2. Antiproliferative activity of couples of dendrimers 1G3 and 1G3-Cu, 2G3 and 2G3-Cu, and 3G3 and 3G3-Cu on KB (A) and HL60 (B) cells after a 72 h exposure, expressed as the percentage of cell growth inhibition at two concentrations (1 and 10 μM) of dendrimers ± SE for two experiments performed in triplicate. Black bar: 10 μM, gray bar: 1 μM.

Figure 3. Growth inhibition effects of 1G3 and 1G3−Cu upon a panel of cell lines. Data are expressed as the mean ± SE of IC50 calculated for two individual determinations in duplicate. *: p < 0.05, **: p < 0.01.

10 for EPC and MCR5 cell lines. Thus noncancer cell lines appeared to be less sensitive than cancer cell lines to 1G3−Cu. The ability of dendrimers to restrict cell proliferation is very attractive and deserves more effort to understand their mode of action. In this respect their capacity to activate the pro-apoptotic cascade is currently underway. In summary, in this study, we paved the synthesis and the antitumor activities of copper-conjugated phosphorus-dendrimers and corresponding monomers. We anticipate that these dendrimers might constitute a new group of antitumor candidates, as suggested by the reported good clinical translation of dendrimers having impressive pharmacodynamic and pharmacokinetic behaviors.6e,f,l 1463



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of bisphosphonate-terminated dendrimers. Eur. J. Org. Chem. 2010, 14, 2759−2767. (e) Ciepluch, K.; Katir, N.; El Kadib, A.; Felczak, A.; Zawadzka, K.; Weber, M.; Klajnert, B.; Lisowska, K.; Caminade, A.-M.; Bousmina, M.; Bryszewska, M.; Majoral, J.-P. Biological properties of new viologen-phosphorus dendrimers. Mol. Pharmaceutics 2012, 9, 448−457. (12) (a) Wang, T.; Guo, Z. Copper in medicine: homeostasis, chelation therapy and antitumor drug design. Curr. Med. Chem. 2006, 13, 525−537. (b) Marzano, C.; Pellei, M.; Tisato, F.; Santini, C. Copper complexes as anticancer agents. Anticancer Agents Med. Chem. 2009, 9, 185−211. (c) Ruiz-Azuara, L.; Bravo-Gomez, M. E. Copper compounds in cancer chemotherapy. Curr. Med. Chem. 2010, 17, 3606−3615. (d) Rodrigues, J.; Jardim, M. G.; Figueira, J.; Gouveia, M.; Tomas, H.; Rissanen, K. Poly(alkylidenamines) dendrimers as scaffolds for the preparation of low-generation ruthenium based metallodendrimers. New J. Chem. 2011, 35, 1938−1943 and references cited therein. (13) Zhao, X.; Loo, S. C. J.; Lee, P. P.; Tan, T. T. Y.; Chu, C. K. Synthesis and cytotoxic activities of chloropyridylimineplatinum(II) and chloropyridyliminecopper(II) surface-functionalized poly(amidoamine) dendrimers. J. Inorg. Biochem. 2010, 104, 105−110. (14) Govender, P.; Renfrew, A. K.; Chavel, C. M.; Dyson, P. J.; Therrien, B.; Smith, G. S. Antiproliferative activity of chelating N,O- and N,N-ruthenium(II) arene functionalised poly(propyleneimine) dendrimer scaffolds. Dalton Trans. 2011, 40, 1158−1167. (15) Cells were plated in 96-well tissue culture with dendrimers dissolved in DMSO (1% final volume). After 72 h exposure, MTS reagent (Promega) was added and incubated for 3 h at 37 °C: the absorbance was monitored at 490 nm, and results are expressed as the inhibition of cell proliferation calculated as the ratio [(1 − (OD490 treated/OD490 control)) × 100]. For IC50 determinations (50% inhibition of cell proliferation) experiments were performed in duplicate.

(6) For recent reviews or papers, see: (a) Gillies, E. R.; Fréchet, J. M. Dendrimers and Dendritic Polymers in Drug Delivery. Drug Discovery Today 2005, 10, 35−43. (b) Caminade, A.-M.; Majoral, J. P. Watersoluble phosphorus-containing dendrimers. Prog. Polym. Sci. 2005, 30, 491−505. (c) McCarthy, T. D.; Karellas, P.; Henderson, S. A.; Giannis, M.; O’Keefe, D. F.; Heery, G.; Paull, J. R. A.; Matthews, B. R.; Holan, G. Dendrimers as drugs: Discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol. Pharmaceutics 2005, 2, 312−318. (d) Griffe, L.; Poupot, M.; Marchand, P.; Maraval, A.; Turrin, C. O.; Rolland, O.; Metivier, P.; Bacquet, G.; Fournie, J. J.; Caminade, A.-M.; Poupot, R.; Majoral, J.-P. Tailored control and optimization of the number of phosphonic acid termini on phosphorus-containing dendrimers for the ex-vivo activation of human monocytes. Chem.Eur. J. 2008, 14, 4836−4850. (e) Wolinsky, J. B.; Mark, W.; Grinstaff, M. Advanced Therapeutic and diagnostic applications of dendrimers for cancer treatment. Drug Delivery Rev. 2008, 60, 1037−1055. (f) Mintzer, M. A.; Grinstaff, M. W. Biomedical applications of dendrimers: a tutorial. Chem. Soc. Rev. 2010, 40, 173. (g) Astruc, D.; Boisselier, E.; Omelas, C. Dendrimer designed for functions: from physical, and supramolecular properties to applications in sensing, catalysis, molecular electronic, photonics, and nanomedicine. Chem. Rev. 2010, 110, 1857−1959. (h) Menjoge, A. R.; Kannan, R. M.; Tomalia, D. A. Dendrimer-Based Drug and Imaging Conjugates: Design Considerations for Nanomedical Applications. Drug Discovery Today 2010, 15, 171−185. (i) Maksimenko, A. V.; Mandrouguine, V.; Gottikh, M. B.; Bertrand, J. R.; Majoral, J.-P.; Malvy, C. Optimisation of dendrimer-mediated gene transfer by anionic oligomers. J. Gene Med. 2003, 5, 61−71. (j) Spataro, G.; Malecaze, F.; Turrin, C. O.; Soler, V.; Duhayon, C.; Elena, P. P.; Majoral, J.-P.; Caminade, A.-M. Designing dendrimers for ocular drug delivery. Eur. J. Med. Chem. 2010, 45, 326−334. (k) El Kazzouli, S.; Mignani, S.; Bousmina, M.; Majoral, J.-P. Dendrimer therapeutics: covalent and ionic attachments. New J. Chem. 2012, 36, 227−240. (l) Khandare, J.; Calderon, M.; Dagia, N. M.; Haag, R. Multifunctional dendritic polymers in nanomedicine: opportunities and challenges. Chem. Soc. Rev. 2012, 41, 2824−2848. (7) The most commonly referenced dendrimers used in nanomedicine are polyamidoamines (PAMAM), poly(L-lysine) scaffold dendrimers (PLL), polyesters (PGLSA-OH), polypropylimines (PPI), poly(2,2bis(hydroxymethyl)propionic acid scaffold dendrimers (bis-MPA), and aminobis(methylenephosphonic acid) scaffold dendrimer. Several are commercially available from various suppliers. The main providers for PAMAM dendrimers (Starbust), polyetherhydroxyl-amine (PEHAM) dendrimers (Priostar), and PPI dendrimers (Astramol) are Sigma Aldrich, National Dendrimers & Nanotechnology, Dendritic Nanotechnologies, and DSM Fine Chemicals. Phosphorus-based dendrimers are commercialized by BDI (BioDendrimer International). (8) Available at http://www.starpharma.com/vivagel (accessed in January 2013). (9) For reviews, see: (a) Gajbhiye, V.; Palanirajan, V. K.; Tekade, R. K.; Jain, N. K. Dendrimers as therapeutic agents: a systematic review. J. Pharm. Pharmacol. 2009, 61, 989−1003. (b) Caminade, A.-M.; Turrin, C.-O.; Majoral, J.-P. Biological properties of phosphorus dendrimers. New. J. Chem. 2010, 34, 1512−1524. (10) Hayder, M.; Poupot, M.; Baron, M.; Nigon, D.; Turrin, C. O.; Caminade, A. M.; Majoral, J.-P.; Eisenberg, R. A.; Fournie, J. J.; Cantagrel, A.; Poupot, R.; Davignon, J. L. A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. Sci. Transl. Med. 2011, 3, 81ra35. (11) (a) Launay, N.; Caminade, A.-M.; Lahana, R.; Majoral, J.-P A general synthetic strategy for neutral phosphorus-containing dendrimers. Angew. Chem., Int. Ed. Engl. 1994, 33, 1589−1592. (b) Galliot, C.; Larré, C.; Caminade, A.-M.; Majoral, J.-P. Regioselective stepwise growth of dendrimer units in the internal voids of a main dendrimer. Science 1997, 277, 1981−1984. (c) Merino, S.; Brauge, L.; Caminade, A.M.; Majoral, J.-P.; Taton, D.; Gnanou, Y. Synthesis and characterization of linear, hyperbranched, and dendrimer-like polymers constituted of the same repeating unit. Chem.Eur. J. 2001, 7, 3095−3105. (d) Cavero, E.; Zablocka, M.; Caminade, A. M.; Majoral, J.-P. Design 1464


Original Multivalent Copper(II)-Conjugated Phosphorus Dendrimers

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