Intended for undergraduate students of organic chemistry, this article addresses synthetic concepts surrounding dendrimers, including the use of protecting groups, functional group interconversions, ...and convergent and divergent synthetic strategies. The review concludes with some of the elementary synthetic transformations used to construct dendrimers.
Derivatives of benzimidazolene-2-thione differing in substitution at the 4 and 5 positions have been synthesized and studied by single-crystal X-ray diffraction and/or X-ray powder diffraction. These ...derivatives include five monosubstituted compounds (1-SX; X = Me, F, Cl, Br, I), four disubstituted compounds (1-SX 2 ; X = Me, F, Cl, Br), the parent dihydro compound (1-SH 2 ), and the naphthyl compound (2-SH 2 ). Five of these molecules gave crystals suitable for single-crystal X-ray diffraction. In all of these crystals, the molecules pack as parallel, hydrogen-bonded tapes. Alternate molecules of a tape occupy two different planes that are separated by approximately 1 Å. The resulting structure is named a stepped tape. These stepped tapes are divided into two classes based on packing: tapes of 1-SH 2 , 1-SMe 2 , and 1-SF pack in flat, parallel planes. Tapes of 2-SH 2 , 1-SF 2 , and 1-SCl 2 pack at an angle; of these, two (2-SH 2 and 1-SF 2 ) incorporate molecules of solvent. None of the structures is isomorphic.
This paper describes the preparation and characterization of four aggregates that are based on the rosette of derivatives of isocyanuric acid (CA) and melamine (M). These aggregates comprise a ...trismelamine, hub(MIm)3, that presents imidazole groups around its periphery; these imidazoles organize zinc tetraphenyl porphyrin (ZnTPP) by coordination of the imidazole to the zinc center. Aggregate 1 forms a single rosette upon mixing 1 equiv of hub(MIm)3 and 3 equiv of CA. Adding 3 equiv of ZnTPP yields 2. Aggregate 3 forms as a stacked bisrosette upon mixing 2 equiv of hub(MIm)3 and 3 equiv of bisCA. Adding 6 equiv of ZnTPP yields 4. The stoichiometries of aggregates 1−4 were obtained by titrating the trismelamines with CA and by titrating the aggregates with ZnTPP. The stoichiometry is defined as the ratio at which additional CA remains insoluble or additional ZnTPP appears as free ZnTPP in the 1H NMR spectrum. Electrospray ionization mass spectrometry (ESI-MS) is compatible with the measured stoichiometries. The structures of these aggregates were determined using variable-temperature 1H NMR spectroscopy; analogous structures were inferred for 5 and 6, the tert-butyl analogues of 1 and 2. The shapes of the traces from gel permeation chromatography (GPC) suggest that imidazole groups destabilize the aggregates when they are not involved in coordination to zinc; that is, the stability seems to be 6 ≈ 4 > 3 and 5 ≈ 2 > 1. A direct comparison of the relative stability of 1, 2, and 5 confirms the results of the GPC analysis: mixing 1 (hub(MIm)3·3CA) with the trismelamine component of 5 (hub(M)3) leads to the formation of a 3:2 mixture of 5:1. Adding ZnTPP to this solution leads to a 3:2 mixture of 5:2 with free trismelamines remaining in solution: 1 is not observed. The results of UV/vis spectroscopy are consistent with the other spectroscopic and chromatographic results and indicate that 3 equiv of ZnTPP are organized around the periphery of 2 and at least 4 equiv around the periphery of 4.
The Information Technology in Science (ITS) Center for Teaching and Learning was a National Science Foundation funded program to provide high‐quality professional development for 7–12th grade science ...teachers. The subgroup on which this paper focuses was immersed in an innovative approach to understanding chemistry of the environment. The group was comprised of 10 high school science teachers representative of science classes taught at all grade levels (9–12th). A team of four university professors led the group. The professors developed inquiry modules and communicated some of the intricacies of their research for adaptation to the participants' classrooms. This paper communicates the successful implementation and lessons learned by scientists during the course of an inquiry‐based curriculum during summer 2005. The process and pace at which the material was covered, qualitative information about the attitudes of the participants towards the curriculum, and implications for professional development from the point of view of the science team leaders will be discussed. Analysis of time spent with participants revealed the progression and type of activities chosen for the professional development experience were effective. Results from informal participant interviews revealed they were most comfortable in incorporating inquiry into their classrooms after having been immersed in it themselves.
A family of generation one, two and three triazine dendrimers differing in their core flexibility was prepared and evaluated for their ability to accomplish gene transfection. Dendrimers and ...dendriplexes were analyzed by their physicochemical and biological properties such as condensation of DNA, size, surface charge, morphology of dendriplexes, toxic and hemolytic effects and ultimately transfection efficiency in L929 and MeWo cells. Flexibility of the backbone was found to play an important role with generation 2 dendrimer displaying higher transfection efficiencies than 25 kDa poly(ethyleneimine) or SuperFect
™
at a lower cytotoxicity level. This result is surprising as PAMAM dendrimers require generations 4 or 5 to become effective transfection reagents. The ability to delineate effects of molecular structure and generation of triazine dendrimers with biological properties provides valuable clues for further modifying this promising class of non-viral delivery systems.
A family of triazine dendrimers, differing in their core flexibility, generation number, and surface functionality, was prepared and evaluated for its ability to accomplish RNAi. The dendriplexes ...were analyzed with respect to their physicochemical and biological properties, including condensation of siRNA, complex size, surface charge, cellular uptake and subcellular distribution, their potential for reporter gene knockdown in HeLa/Luc cells, and ultimately their stability, biodistribution, pharmacokinetics and intracellular uptake in mice after intravenous (iv.) administration. The structure of the backbone was found to significantly influence siRNA transfection efficiency, with rigid, second generation dendrimers displaying higher gene knockdown than the flexible analogues while maintaining less off-target effects than Lipofectamine. Additionally, among the rigid, second generation dendrimers, those with either arginine-like exteriors or peripheries containing hydrophobic functionalities mediated the most effective gene knockdown, thus showing that dendrimer surface groups also affect transfection efficiency. Moreover, these two most effective dendriplexes were stable in circulation upon intravenous administration and showed passive targeting to the lung. Both dendriplex formulations were taken up into the alveolar epithelium, making them promising candidates for RNAi in the lung. The ability to correlate the effects of triazine dendrimer core scaffolds, generation number, and surface functionality with siRNA transfection efficiency yields valuable information for further modifying this non-viral delivery system and stresses the importance of only loosely correlating effective gene delivery vectors with siRNA transfection agents.
The physicochemical characteristics,
in vitro
properties, and
in vivo
toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and ...twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6–19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former ~40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs
in vitro
in human, rat, and mouse plasma and is non-linear, ranging from 7–20% cumulative release over a 48 hour incubation period. The construct is 2–3 orders of magnitude less toxic than Taxol
®
by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane
®
in LS174T cells. Both Taxol® and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation
in vitro
, but does appear to reduce collagen-induced platelet aggregation
in vitro
. Furthermore, the dendrimer formulation slightly activates the complement system
in vitro
due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50 and 100 mg paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non-tumor bearing athymic nude mice. The construct showed
in vivo
toxicity comparable to Abraxane. Both formulations were found to be non-toxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort.
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