Synthesis of Triazine Dendrimers - JST
Synthesis of Triazine Dendrimers
Lirias: The use of 1,3,5-triazines in dendrimer synthesis
A polystyrene–poly(ethylene glycol) (PS–PEG) resin-supported triazine-based polyethyleneamine dendrimer copper catalyst (PS–PEG-TD2–CuSO4) was prepared and characterized by means of CP-MAS NMR, UV–vis/NIR, FTIR, SEM-EDX, XPS, and ICP-AES analyses. PS–PEG-TD2–CuSO4 was highly active in the Huisgen 1,3-dipolar cycloaddition of various organic azides with alkynes in water as well as the three-component reaction of alkynes, alkyl bromides, and sodium azide under batch conditions to give the corresponding triazoles in excellent yields with high recyclability of the catalyst. TEM analysis suggested that the copper nanoparticles generated in situ through reduction of PS–PEG-TD2–CuSO4 with sodium ascorbate serve as the active catalytic species. The application of PS–PEG-TD2–CuSO4 catalyst in a continuous-flow Huisgen reaction for the synthesis of 1,2,3-triazoles was also examined. The cycloaddition of organic azides with alkynes was completed within 22 s in the continuous-flow system containing PS–PEG-TD2–CuSO4 to give the corresponding triazoles in up to 99% yield. Moreover, the continuous-flow system accomplished the long-term continuous-flow cycloaddition for 48 h producing 10 g of a triazole as well as the successive flow reaction producing various kinds of triazoles.
The synthesis of all dendrimers used in this study proceeded via a divergent strategy originating from cyanuric chloride. The rigid, first generation dendrimer was synthesized by reacting a tris(piperazyl) triazine core with MCT1, followed by deprotection. The rigid, second generation dendrimer, G2-1, was synthesized as previously described (). To form the third generation rigid dendrimer, G3-1, the rigid, deprotected G1-dendrimer, G1-C was reacted with di(Boc-piperazyl)monochlorotriazine. This second generation structure was deprotected and reacted with MCT1 to form the protected third generation compound, which was deprotected using HCl (). A detailed description of the synthesis is provided in the section.
Kilogram Scale Synthesis of a Triazine-based Dendrimer …
Non-viral vectors such as cationic liposomes, linear and branched polycations and dendrimers have been shown to be effective transfection agents and offer advantages over viral vectors regarding safety and manufacturing. Several non-viral gene delivery systems based on poly(amidoamine) (PAMAM) (–), poly(propylene imine) (PPI) (, ), and poly(ethylene imine) (PEI) (, ) have yielded efficient transfection in vivo with relatively low toxicity. The potential of triazine dendrimers as gene delivery systems is largely unexplored, but has been described by us in a study involving generation 2 rigid structures (), which reveal an optimized peripheral group for further study. These dendrimers may be attractive candidates as they can be synthesized in high yields via a divergent strategy that creates multiple surface functionalities in a completely monodisperse manner (). In addition, triazine dendrimers show low toxicity, both in vitro and in vivo: mice tolerate i.p. doses up to 40 mg/kg (). This level of toxicity is comparable to PAMAM () suggesting that triazine dendrimers could be considered as a platform for transfection studies. Here, the physicochemical properties, cytotoxicities and transfection efficiencies of a panel of triazine dendrimers were evaluated to establish structure function relationships. The effect of dendrimer size (generations) as well as core structure is probed in an attempt to maximize transfection efficiency. Increasing generation increases size and the number of available cations. Changing the composition of the core affords dendrimers that differ in the flexibility, a characteristic that is thought to influence interactions with p-DNA (). The dendrimers used in this study are shown in . Here we present results from the synthesis, physicochemical and biological in vitro evaluation of a panel of 5 triazine dendrimers and compare them to commercially available PAMAM dendrimers of different generations to define structural parameters such as generation and core flexibility for the design of triazine dendrimers as non-viral gene delivery systems.
The flexible core dendrimer, F2-1, was synthesized by reacting cyanuric chloride with mono-Boc-protected O,O′-bis(3-aminopropyl)diethylene glycol. This core was deprotected with HCl, reacted with Boc-piperazyl-dichlorotriazine, and capped with Boc-piperazine. After removal of the protecting groups with HCl, the compounds were reacted with MCT1 and deprotected to form the flexible, second generation dendrimer, F2-1 (). A detailed description of the synthesis is provided in the section.
Synthesis and characterization of a triazine dendrimer ..
Kilogram-scale synthesis of a triazine-based dendrimer relies on reaction of the dichlorotriazine monomer with the amine terminated dendrimer to afford a poly(monochlorotriazine) dendrimer.
The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkers--dipiperidine trismethylene, piperazine, and aminomethylpiperidine--were used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2'-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by (1)H and (13)C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5-8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (~6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg.
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Robust, Efficient, and Orthogonal Synthesis of …
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Finally, the second generation bow-tie structure, B2-1, was synthesized by reacting di(Boc-piperazyl)monochlorotriazine with O,O′-bis(3-aminopropyl)diethylene glycol. This core structure was deprotected with HCl and reacted with di(Boc-piperazyl)monochlorotriazine to form a first generation bow-tie structure. This structure was deprotected, reacted with MCT1, and deprotected again to afford the dendrimer B2-1 (). A detailed description of the synthesis is provided in the section.
Development and Characterization of Triazine Based Dendrimers for ..
As the products of multistep organic syntheses, triazine dendrimers allow us access to well-defined structures to investigate structure-activity relationships such as the influence of size and backbone structure on transfection efficiency and cytotoxicity. For this purpose, a preliminary panel of dendrimers was synthesized consisting of different generations (G1, G2, G3) with a rigid backbone and a common surface group (), yielding 6, 12 or 24 amino-groups in the periphery. With each increase in generation number, the number of primary amino groups presented in the periphery doubles.
Triazine based Dendrimers - MDPI
and and and and and and and and and (2013) Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups. Molecular pharmaceutics, 10 (12). pp. 4452-4461. ISSN 1543-8384
Dendrimer is a compound word, ..
In addition to generation number, the flexibility of the core could hypothetically affect transfection efficiency by influencing the distribution and accessibility of the peripheral groups for interacting with p-DNA (). The role of flexibility has been supported experimentally by Szoka who showed enhanced transfection efficiency resulting from fragmentation of PAMAM dendrimers (). In this study, this effect was investigated with second generation triazine dendrimers, each having differing core flexibilities (G2-1, F2-1, B2-1). Synthetic yields and NMR data are provided within the .
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