Window of reactivity

Window of Reactivity (Lability). The relationship between tissue distribution and kinetic reactivity of the chloroammlne-platinum(II) complexes gives credence to the Concept of the Window of Reactivity. Although Ideally applied to isostructural complexes of the same net charge, this concept is of sufficient generality to be applicable to this series of complexes. Accord- 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

Pt-195m-labeled chloroammlneplatlnum(II) complexes have been synthesized on a microscale and used to study the distribution of these complexes in normal rats. Qualitative correlations of the distribution data, principally at 24 h post-injection, with available physico-chemical, biological, and structure-antitumor activity data were carried out to gain Insight into the nature, fate, and potential utility of these and related agents in biological systems. Highlights of the results are as follows. 

Tissue distribution patterns are well-defined and reflect the unique chemistry of these substitution-inert complexes. 

The order of tissue retention at 24 h post-injection was Kidney liver lung genitals spleen bladder 

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In the early development of analogs of the platinum compounds, complexes with windows of reactivity similar to the platinum complexes were examined extensively. Whereas direct Ni and Pd analogs of Pt complexes are too kinetically reactive to be of use as drugs, Ir and Os ammine... 

In addition to intermolecular reactions, C-glycosides can also be synthesized by intramolecular sequences. A radical cyclization is a very fast reaction, in particular 5-exo-trig cyclizations. Thus, intermediate anomeric radicals have only a short time window of reactivity before undergoing the desired cyclization. 

On the other hand, RD, RA, and RE have a number of specific features that should be considered with care and described by different approaches. Before going into detail, it is worthy to note that the operating window of reactive separations may be somewhat limited, since these operations are feasible only if they allow for both separation and reaction within the same range of temperature and pressure and, on the other hand, for the safe operation from the constructional point of view (Figure 2). 

Figure 9. Illustration of the window of reactivity concept using data for cis- and tians-[Pt(NH,)iCl,] and [Pt(NH3)f]Ch...

The high tissue uptake but low antitumor activity for charged species indicates that uptake per ee is necessary but not a sufficient criterion of activity and that other factors such as the intrinsic reactivity and the nature of binding to the target site are more critical in eliciting antitumor activity. Comparative data for trcme-[Pt(NH3)2Cl2l and [Pt(NH3)i,]Cl2 validate the "Concept of the Window of Reactivity."... 

Cleare and Hoeschele [15] first suggested that there is a "window of reactivity" for metal complexes to display antitumour activity. Reaction times of 2-3 hours appear to be important. Thus Pd(II) complexes are too reactive, but Ru(II) complexes have suitable substitution rates and some of these complexes have been shown to display interesting antitumour activity. 

The administration of robust complexes such as those of Pt or Au will be of use when their reactivity with the target is pharmacokinetically appropriate — the window of reactivity must be recognised and will depend on chemical factors such as hydrolysis and ligand exchange as well as uptake and distribution. Uptake of metal complexes may be best for neutral species, since no transport process need be activated but it is well to remember that this is not an absolute requirement. The charged amine complexes, close analogues of cisplatin, enter cells (Chapter 3.1) and indeed lipophilicity may enhance this uptake an example is the ruthenium (II) chelate of (3,4,7,8-)tetramethyl-l,10-phenanthroline (Chapter 6.1.3). 

A comparison of platinum group metal complexes is illustrative of the relatively narrow window of reactivity and stability which generates complexes with suitable antitumour activity. Table 6.1 collects some comparative data of structurally analogous complexes, containing only ammonia and chloride ligands. The palladium complex, like the octahedral iridium analogue, shows little activity, while those of rhodium and ruthenium are somewhat intermediate. Palladium complexes are more labile than those of platinum, reacting approximately 10 times faster, and it is reasonable to accept that the palladium complex will be too reactive in vivo for any... 

Chemical reactivity of unfunctionalized organosilicon compounds, the tetraalkylsilanes, are generally very low. There has been virtually no method for the selective transformation of unfunctionalized tetraalkylsilanes into other compounds under mild conditions. The electrochemical reactivity of tetraalkylsilanes is also very low. Kochi et al. have reported the oxidation potentials of tetraalkyl group-14-metal compounds determined by cyclic voltammetry [2]. The oxidation potential (Ep) increases in the order of Pb < Sn < Ge < Si as shown in Table 1. The order of the oxidation potential is the same as that of the ionization potentials and the steric effect of the alkyl group is very small. Therefore, the electron transfer is suggested as proceeding by an outer-sphere process. However, it seems to be difficult to oxidize tetraalkylsilanes electro-chemically in a practical sense because the oxidation potentials are outside the electrochemical windows of the usual supporting electrolyte/solvent systems (>2.5 V). 

Table I also presents the temperature at which this exothermal process starts (as Tg) and at which it ends (as Tg). The difference Tg- T can be considered as being the processing window of the thermally reactive oligomers, and is also listed in Table I.

There are a number of non-electrochemical techniques that have proven invaluable in combination with electrochemical results in understanding the chemistry and the kinetics. Laser flash photolysis (LFP) is a well-established technique for the study of the transient spectroscopy and kinetics of reactive intermediates. The technique is valuable for the studying of the kinetics of the reactions of radical anions, particularly those that undergo rapid stepwise dissociative processes. The kinetics of fragmentation of radical anions can be determined using this method if (i) the radical anion of interest can be formed in a process initiated by a laser pulse, (ii) it has a characteristic absorption spectrum with a suitable extinction coefficient, and (iii) the rate of decay of the absorption of the radical anion falls within the kinetic window of the LFP technique typically this is in the order of 1 x 10" s to 1 X 10 s . 

It is of interest primarily for very uniform ultra-thin films and coatings (0.002-5 mils) in applications such as electrical resistors, thermistors, thermocouples, stator cores, connectors, fast-sensing probes, photo cells, memory units, dropwise steam condensers for recovery of sea water, pellicles for beam splitters in optical instruments, windows for nuclear radiation counters, panels for micrometeorite detection, dielectric supports for planar capacitors, encapsulation of reactive powders, and supports in x-ray and optical work. Any significant growth would depend upon a major breakthrough in process techniques and a consequent lowering in price. 

Table 1 gives an overview of the possible applications of reactive distillation reported in the literature. Very few of them have been realized so far on the commercial scale. One of the common factors that hinders a broader application of reactive distillation is a small feasible operation window. The overlap region in the pressure-temperature domain, in which chemical reaction and separation and apparatus design are feasible, is usually quite narrow (see Figure 2 in Chapter 9). A possible remedy for this limitation is sought in the development of new types of catalysts that would allow one to significantly broaden the feasible operation window for chemical reaction. 

Electrochemical studies are usually performed with compounds which are reactive at potentials within the potential window of the chosen medium i.e. a system is selected so that the compound can be reduced at potentials where the electrolyte, solvent and electrode are inert. The reactions described here are distinctive in that they occur at very negative potentials at the limit of the cathodic potential window . We have focused here on preparative reductions at mercury cathodes in media containing tetraalkylammonium (TAA+) electrolytes. Using these conditions the cathodic reduction of functional groups which are electroinactive within the accessible potential window has been achieved and several simple, but selective organic syntheses were performed. Quite a number of functional groups are reduced at this limit of the cathodic potential window . They include a variety of benzenoid aromatic compounds, heteroaromatics, alkynes, 1,3-dienes, certain alkyl halides, and aliphatic ketones. It seems likely that the list will be increased to include examples of other aliphatic functional groups. 

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