For two decades, methods for the synthesis and characterization of dendrimers based on 1,3,5-triazine have been advanced by the group. Motivated by the desire to generate structural complexity on the ...periphery, initial efforts focused on convergent syntheses, which yielded pure materials to generation three. To obtain larger generations of dendrimers, divergent strategies were pursued using iterative reactions of monomers, sequential additions of triazine and diamines, and ultimately, macromonomers. Strategies for the incorporation of bioactive molecules using non-covalent and covalent strategies have been explored. These bioactive materials included small molecule drugs, peptides, and genetic material. In some cases, these constructs were examined in both in vitro and in vivo models with a focus on targeting prostate tumor subtypes with paclitaxel conjugates. In the materials realm, the use of triazine dendrimers anchored on solid surfaces including smectite clay, silica, mesoporous alumina, polystyrene, and others was explored for the separation of volatile organics from gas streams or the sequestration of atrazine from solution. The combination of these organics with metal nanoparticles has been probed. The goal of this review is to summarize these efforts.
This review summarizes the in vivo assessmentpreliminary, preclinical, and clinicalof chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic ...quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and hydrolysis under physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity. Binding inhibits DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or noncovalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.
The use of triazine dendrimers as drug delivery systems benefits from their synthetic versatility and well-defined structure. Triazine dendrimers can be designed and readily synthesized to display ...orthogonally functional surfaces that facilitate post-synthetic manipulation such as attachment of drug, PEGylation, and/or the installation of ligands or reporting groups. The synthesis is scalable, and large generations can be accessed. To date, triazine dendrimers have been probed for a variety of medicinal applications including drug delivery with an emphasis on cancer, nonviral DNA and RNA delivery systems, in sensing applications, and as bioactive materials. Specifically, triazine adducts with paclitaxel, camptothecin, brefeldin A, and desferrioxamine have been prepared and assessed. Paclitaxel constructs show promising activity in vivo. The use of these materials in fluorescence-based glucose sensors is being pursued. Glycosylated triazine dendrimers interfere with signal transduction in the Toll-4 receptor pathway.
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Dendrimers are attractive macromolecules for a broad range of applications owing to their well-defined shapes and dimensions, highly branched and globular architectures, and opportunities for ...exploiting multivalency. Triazine dendrimers in particular offer advantages such as ease of synthesis, stability, well-defined spherical structure, multivalency, potential to achieve acceptable drug loadings, and low polydispersity. In this study, the potential utility of alkyne-azide "click" cycloadditions of first-, second-, and third-generation triazine dendrimers containing three or six alkynyl groups with benzyl azide was examined using copper catalysts. "Click-and-grow" and "grow-then-click" strategies were employed. For the first- and second- generation dendrimers, the desired triazole derivatives were obtained in high yields and purified by simple reprecipitation without column chromatography; however, some difficulties were observed in the preparation of third-generation dendrimers. The desired reaction proceeded under microwave irradiation as well as with simple heating. This click chemistry can be utilized for various melamine dendrimers that are fabricated with other amine linkers.
Amine-substituted s-triazines display hindered rotation around the triazine-N bond. While this barrier, ΔG ‡, has been measured to be between 15.1 and 17.7 kcal/mol for neutral triazines, the impacts ...that solvent and protonation state have not been addressed. Using a dimethylamine substituent as a reporter, ΔG ‡ was measured to be 17.5–19.3 kcal/mol upon protonation across a range of solvents (D2O, DMSO-d 6, MeCN-d 3, MeOD-d 4, tetrahydrofuran-d 8, trifluoroethanol-d 3). Furthermore, ΔG ‡ increases as the solvent dielectric decreases (p < 0.01). This trend is consistent with the role that solvent plays in stabilizing the increased charge density on the triazine ring resulting from a loss of conjugation with the dimethylamine substituent. Across these solvents, ΔG ‡ for the neutral molecule is smaller by ∼2–3 kcal/mol, ranging from 15.3–16.1 kcal/mol. In pyridine, ΔG ‡ does not correlate with the solvent dielectric for the “protonated” model. The lower barrier is attributed to competitive protonation: the pK a of the protonated triazine (∼6) is similar to that of protonated pyridine-d 5 (5.8). As additional acid is added, ΔG ‡ increases. Adding additional acid to the protonated model in D2O or DMSO-d 6 does not significantly affect ΔG ‡.
A small library of dendrimers was prepared from a common precursor that is available in 5 g scale in five linear steps at 56% overall yield. The precursor is a generation three dendrimer that ...displays 48 peripheral sites by incorporating AB4 surface groups. Manipulation of these sites provided six dendrimers that vary in the chemistry of the surface group (amine, guanidine, carboxylate, sulfonate, phosphonate, and PEGylated) that were evaluated for hemolytic potential and cytotoxicity. Cationic dendrimers were found to be more cytotoxic and hemolytic than anionic or PEGylated dendrimers. The PEGylated dendrimer was evaluated for acute toxicity in vivo. No toxicityneither mortality nor abnormal blood chemistry based on blood urea nitrogen levels or alanine transaminase activitywas observed in doses up to 2.56 g/kg ip and 1.28 g/kg iv.
Triazine and PAMAM dendrimers of similar size and number of cationic surface groups were compared for their ability to promote platelet aggregation. Triazine dendrimers (G3, G5 and G7) varied in ...molecular weight from 8 kDa-130 kDa and in surface groups 16-256. PAMAM dendrimers selected for comparison included G3 (7 kDa, 32 surface groups) and G6 (58 kDa, 256 surface groups). The treatment of human platelet-rich plasma (PRP) with low generation triazine dendrimers (0.01-1 µM) did not show any significant effect in human platelet aggregation in vitro; however, the treatment of PRP with larger generations promotes an effective aggregation. These results are in agreement with studies performed with PAMAM dendrimers, where large generations promote aggregation. Triazine dendrimers promote aggregation less aggressively than PAMAM dendrimers, a factor attributed to differences in cationic charge or the formation of supramolecular assemblies of dendrimers.
A readily and rapidly accessible triazine dendrimer was manipulated in four steps with 23% overall yield to give a construct displaying four maleimide groups and DOTA. The maleimide groups of the ...dendrimer are sensitive to hydrolysis under basic conditions. The addition of up to four molecules of water can be observed via mass spectrometry and HPLC. The evolution in the alkene region of the ¹H-NMR--the transformation of the maleimide singlet to the appearance of two doublets--is consistent with imide hydrolysis and not the Michael addition. The hydrolysis events that proceeded over hours are sufficiently slower than the desired thiol addition reactions that occur in minutes. The addition of thiols to maleimides can be accomplished in a variety of solvents. The thiols examined derived from cysteine and include the protected amino acid, a protected dipeptide, and native oligopeptides containing either 9 or 18 amino acids. The addition reactions were monitored with HPLC and mass spectrometry in most cases. Complete substitution was observed for small molecule reactants. The model peptides containing nine or eighteen amino acids provided a mixture of products averaging between 3 and 4 substitutions/dendrimer. The functionalization of the chelate group with gadolinium was also accomplished easily.
In the absence of preorganization, macrocyclization reactions are often plagued by oligomeric and polymeric side products. Here, a network of hydrogen bonds was identified as the basis for ...quantitative yields of macrocycles derived from the dimerization of monomers. Oligomers and polymers were not observed. Macrocyclization, the result of the formation of two hydrazones, was hypothesized to proceed in two steps. After condensation to yield the monohydrazone, a network of hydrogen bonds formed to preorganize the terminal acetal and hydrazine groups for cyclization. Experimental evidence for preorganization derived from macrocycles and acyclic models. Solution NMR spectroscopy and single-crystal X-ray diffraction revealed that the macrocycles isolated from the cyclization reaction were protonated twice. These protons contributed to an intramolecular network of hydrogen bonds that engaged distant carbonyl groups to realize a long-range order. DFT calculations showed that this network of hydrogen bonds contributed 8.7 kcal/mol to stability. Acyclic models recapitulated this network in solution. Condensation of an acetal and a triazinyl hydrazine, which adopted a number of conformational isomers, yielded a hydrazone that adopted a favored rotamer conformation in solution. The critical hydrogen-bonded proton was also evident. DFT calculations of acyclic models showed that the rotamers were isoenergetic when deprotonated. Upon protonation, however, energies diverged with one low-energy rotamer adopting the conformation observed in the macrocycle. This conformation anchored the network of hydrogen bonds of the intermediate. Computation revealed that the hydrogen-bonded network in the acyclic intermediate contributed up to 14 kcal/mol of stability and preorganized the acetal and hydrazine for cyclization.
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