Dendritic systems

To compare the disassembly rate of the above dendritic systems, we synthesized AB3 molecules 18 and 19 (Fig. 5.10). Both the molecules are designed for activation by PGA and have three units of tryptophan as a model drug. Tryptophan was used for initial evaluation as it contains a strong UV chromophore, allowing us to monitor the disassembly reaction. 

We decided to apply the elimination-based dendritic system to the synthesis of an anticancer prodrug and to evaluate it in a tumor cell cytotoxicity assay. Dendritic prodrugs 20 and 21 were synthesized with the chemotherapeutic drug melphalan as a tail unit and a trigger that is activated by PGA (Fig. 5.14). 

FIGURE 5.16 AB3 self-immolative dendritic system with diphenylalanine end units and a trigger designed for activation by PGA. 

We also wanted to evaluate the disassembly of our dendritic system under physiological conditions. Thus, we synthesized a self-immolative AB6 dendron 32 with water-soluble tryptophan tail units and a phenylacetamide head as a trigger (Fig. 5.26) to evaluate disassembly in aqueous conditions. The phenylacetamide is selectively cleaved by the bacterial enzyme penicillin G amidase (PGA). The trigger was designed to disassemble through azaquinone methide rearrangement and cyclic dimethylurea elimination to release a phenol intermediate that will undergo six quinone methide elimination reactions to release the tryptophan tail units. 

Probably the best example of the manifestation of self-assembly processes in dendritic systems via H-bonds is seen in the recent work of Zimmerman et al. [156]. Dendritic wedges possessing tetraacid moieties (67) self-assembling into a hexameric, disc-like framework (68) was confirmed by SEC and -NMR studies. The tetraacid unit (69) is known to form cyclic as well as linear aggregates in solution via carboxylic acid dimerization (Fig. 30). However, with incorporation of larger dendritic wedges on 69, the hexamer form is preferred. 

Under carefully adjusted experimental conditions unmodified catalysts can be used in nanofiltration coupled homogeneous catalysis. Also non-dendritic but nanosized rigid catalytic systems can be retained by nanofiltration membranes. In this section, unmodified catalysts and rigid non-dendritic systems applied in continuous catalysis will be discussed. 

To characterize dendrimers, analytical methods used in synthetic organic chemistry as well as in macromolecular chemistry can be applied. Mass spectrometry and NMR spectroscopy are especially useful tools to estimate purity and structural perfection. To get an idea of the size of dendrimers, direct visualization methods such as atomic force microscopy (AFM) and transmission electron microscopy (TEM), or indirect methods such as size exclusion chromatography (SEC) or viscosimetry, are valuable. Computer aided simulation also became a very useful tool not only for the simulation of the geometry of a distinct molecule, but also for the estimation of the dynamics in a dendritic system, especially concerning mobility, shape-persistence, and end-group disposition. 

This section summarizes work carried out on polynuclear complexes containing M(bpy)2 units, an area in which there is much interest, in particular with respect to energy transfer. Dendritic systems are excluded from this review, but are covered elsewhere in CCC The complexes-as-ligands strategy is commonly exploited for the controlled construction of multinuclear complexes and examples are seen in this section. 

In periphery-functionalized dendritic catalysts, the functional groups at the surface determine the solubility and miscibility and thus the precipitation properties. Many dendrimers functionalized with organometallic complexes do not dissolve in apolar solvents, and the presence of multiple metal centers at the periphery facilitates precipitation upon addition of this type of solvent. It is emphasized that the use of dendrimer-immobilized catalysts with the goal of recovery through precipitation is worthwhile only if the tendency to precipitation of the dendritic system exceeds that of its non-dendritic equivalent. 

The affinity of Cgo towards carbon nucleophiles has been used to synthesize polymer-bound Cgo [120] as well as surface-bound Cjq [121]. Polymers involving G q [54, 68, 69] are of considerable interest as (1) the fullerene properties can be combined with those of specific polymers, (2) suitable fullerene polymers should be spin-coatable, solvent-castable or melt-extrudable and (3) fullerene-containing polymers as well as surface-bound Cgo layers are expected to have remarkable electronic, magnetic, mechanical, optical or catalytic properties [54]. Some prototypes of polymers or solids containing the covalently bound Cjq moiety are possible (Figure 3.11) [68,122] fullerene pendant systems la with Cjq on the side chain of a polymer (on-chain type or charm bracelet ) [123] or on the surface of a solid Ib [121], in-chain polymers II with the fullerene as a part of the main chain ( pearl necklace ) [123], dendritic systems III, starburst or cross-link type IV or end-chain type polymers V that are terminated by a fullerene unit For III and IV, one-, two-and three-dimensional variants can be considered. In addition, combinations of all of these types are possible. 

Dendrimers Terminated with Cobaltocenium and Ferrocene-Cobaltocenium Units Like ferrocene, cobaltocenium is an excellent organometallic moiety to incorporate in or functionalize dendritic systems. As already discussed, it is indeed isoelectronic with ferrocene, highly stable, positively charged complex, which undergoes a reversible monoelectronic reduction to yield the neutral cobaltocene. 

Some particularly elegant applications of this methodology are used in the assembly of dendritic systems. For example, the ruthenium(n) complex of 4,4 -dichloro-2,2 -... 

The simplest synthetic approach to the preparation of monofunctional dendritic systems is to functionalise the periphery of existing molecular scaffolds, generally constructed by divergent or convergent growth (Fig. 3.2, Route a) or b), respectively). 

The properties of a dendrimer are determined not only by the specific properties of its functional units, but also by their number and structural variety, and by cooperative effects between different functional units. A number of special applications and the development of substances suitable for mimicking biological systems [53] require such multifunctional dendritic systems with more than one kind of functionality. 

Owing to their spheroidal molecular shape, fullerenes represent attractive functional core units for light-harvesting dendritic systems. In fullerene dendrimers of... 

In extending these concepts to very large dendritic systems, it is likely that a wider range of metal ions and ligands will become necessary in order to give a smoothly graduated energy-transfer cascade. 

In another example of the dendronization of solid supports, Rhee et al. described the design of silica-supported chiral dendritic catalysts for the en-antioselective addition of diethylzinc to benzaldehyde (Fig. 28) [60-62], The immobilized dendritic systems were formed in two different ways one by stepwise propagation of dendrimers and the other by direct immobilization... 

Although this notation can be applied to diverse structures, the following rules and examples have been confined to very simple dendritic systems. 

Although strictly not a dendritic system, Agar et al.[75] have reported the preparation of copper(n) phthalocyaninate substituted with eight 12-membered tetraaza macrocycles as well as its nickel(n), copper(n), cobalt(n), and zinc(n) complexes. Thus, the use of the l,4,7-tritosyl-l,4,7,10-tetraazacyclododecane offers a novel approach to the 1 — 3 branching pattern and a locus for metal ion encapsulation. 

Whereas the well-characterized, perfect (or nearly so) structures of dendritic macromolecules, constructed in discrete stepwise procedures have been described in the preceding chapters, this Chapter reports on the related, less than perfect, hyperbranched polymers, which are synthesized by means of a direct, one-step polycondensation of A B monomers, where x > 2. Flory s prediction and subsequent demonstration 1,2 that A B monomers generate highly branched polymers heralded advances in the creation of idealized dendritic systems thus the desire for simpler, and in most cases more economical, (one-step) procedures to the hyperbranched relatives became more attractive. 

Padilla De Jesus OL et al (2002) Polyester dendritic systems for drug delivery applications in vitro and in vivo evaluation. Bioconjug Chem 13 453—461... 

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