The importance of water solubility

The importance of water solubility in drug action means that one of the medicinal chemist s development targets for a new drug is to develop analogues that have the required degree of water solubility. 

The importance of water soluble polymers such as the polyacrylamides is well established but only now are fundamental data on these systems beginning to accumulate. The unperturbed dimensions of these polymers tend to depend on the lateral substituent, and specific interactions are thought to produce large chain expansions with a corresponding low chain flexibility. In some cases the specific interactions can lead to a system exhibiting a pseudo-lower critical-solution temperature. The characteristic parameter C for polyacrylamide in water has also been reassessed in the belirf that the published value is too high. The excluded volume parameter and unperturbed dimensions have also been measured for poly ( -1,1-dimethyl-3-oxobutylacrylamide) in MEK. Many of the papers mentioned in Table 1 contain additional data on the sedimentation behaviour and thermodynamic parameters. 

There are, indeed, many biological implications that have been triggered by the advent of fullerenes. They range from potential inhibition of HIV-1 protease, synthesis of dmgs for photodynamic therapy and free radical scavenging (antioxidants), to participation in photo-induced DNA scission processes [156, 157, 158, 159, 160, 161, 162 and 163]. These examples unequivocally demonstrate the particular importance of water-soluble fullerenes and are summarized in a few excellent reviews [141, 1751. 

Indeed, these reactions proceed at 25 °C in ethanol-aqueous media in the absence of transition metal catalysts. The ease with which P-H bonds in primary phosphines can be converted to P-C bonds, as shown in Schemes 9 and 10, demonstrates the importance of primary phosphines in the design and development of novel organophosphorus compounds. In particular, functionalized hydroxymethyl phosphines have become ubiquitous in the development of water-soluble transition metal/organometallic compounds for potential applications in biphasic aqueous-organic catalysis and also in transition metal based pharmaceutical development [53-62]. Extensive investigations on the coordination chemistry of hydroxymethyl phosphines have demonstrated unique stereospe-cific and kinetic propensity of this class of water-soluble phosphines [53-62]. Representative examples outlined in Fig. 4, depict bidentate and multidentate coordination modes and the unique kinetic propensity to stabilize various oxidation states of metal centers, such as Re( V), Rh(III), Pt(II) and Au(I), in aqueous media [53 - 62]. Therefore, the importance of functionalized primary phosphines in the development of multidentate water-soluble phosphines cannot be overemphasized. 

This chapter is written for a medicinal chemistry audience. The focus is on the importance of drug solubility in water and in dimethylsulfoxide (DMSO) in the types of activities likely to be of interest to medicinal chemists. The emphasis is on the discovery stage as opposed to the development stage. The reader will find numerous generalizations and rules of thumb relating to solubility in a drug discovery setting. 

The content of heavy metals in Steppe soils is tightly connected with their contents in geological rocks. In formation of soil exposure pathways in Desert ecosystems, water-soluble forms of these metals play the most important role. We can see an analogy between the increasing content of elements in soil dead organic matter as a function of decreasing water excess in Forest ecosystems and the increasing content of water-soluble species of chemical elements in the soils of Dry Steppe and Desert ecosystems as a function of enhanced aridity. The accumulation of water-soluble species occurs in the upper horizon for almost all elements, with exception of strontium. The main factor responsible for the accumulation of water-soluble forms is connected with evapotranspiration. 

Hydrogenation of the carbonyl function is an important synthetic transformation and can be catalyzed by complexes of several transition metals including -among others- Co, Rh, Ru, Ir, and Os. In aqueous organometallic catalysis the first examples were given by the hydrogenation of water-soluble 2-oxo-carboxylic acids, 1,3-dihydroxyacetone and fmctose [47-54], later the same substrates were also used for testing new catalysts [29]. 

Hydrocyanation of olefins and dienes is an extremely important reaction [32] (about 75 % of the world s adiponitrile production is based on the hydrocyanation of 1,3-butediene). Not surprisingly, already one of the first Rhone Poluenc patents on the use of water soluble complexes of TPPTS described the Ni-catalyzed hydration of butadiene and 3-pentenenitrile (Scheme 9.10). The aqueous phase with the catalyst could be recycled, however the reaction was found not sufficiently selective. 

One of the important mechanisms by which orally administered steroids are inactivated involves the formation of water-soluble derivatives at the 17 position, a process that is greatly reduced in 17a-alkyl-17(3-hydroxy derivatives. Extensive use of the resulting orally active compounds has since revealed that 17 alkylation also leads to increased liver toxicity. Preparation of the first of these compounds, nor-methandrolone (32-3), starts by addition of methylmagnesium iodide to estrone methyl ether (9-1) to give the 17a methyl derivative. Birch reduction followed by acid hydrolysis leads to normethandrolone (32-3) [16]. 

ISO 4621 (1986) also specifies analytical methods. Usually, analysis of chromium and the byproducts is preceded by melting with soda and sodium peroxide. The content of water-soluble or acid-soluble chromium is becoming important from the toxicological and ecological point of view. It is determined according to DIN 53 780 with water, or according to ISO 3856, part 1 with 0.1 mol/L hydrochloric acid. 

Because NDIs are a popular choice of acceptor in electron transfer studies, the NDI redox and photophysical properties are well documented and, more importantly, absorbance and fluorescence maxima are known for both the neutral and radical anion species. This has led the group of Miller [25] to exploit their properties in forming conducting wires based on the doping of water-soluble NDIs by peripheral modification on the polyamidoamine (PAMAM) dendrimers 19 (Figure 11.9). 

It was at the turn of the twentieth century that the importance of lipid solubility in drug action was also independently described by Meyer and Overton (the significance of the oil/water partition coefficient was discussed in Chapter 2). The importance of lipid solubility in drug action subsequently became manifested in the lipoid theory of cellular depression. In essence, this theory correlated a pharmacological effect (e.g., CNS depression) with a physical property (i.e., lipid solubility) rather than a structure-activity relationship. In the process, the theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anesthetic classes of drugs (see Chapter 11). Today, we realize the limitations of the lipoid theory and appreciate that the distinction between physical and chemical factors is illusory, since chemical structure is a determinant of physical properties. 

Hydrophobic interactions are such an important driving force in the folding of water-soluble globular proteins that we can formulate the general rule hydrophobic residues tend to be buried in the interior of proteins which minimizes their exposure to water. 

Flocculants— The need to separate undesired. solid particles finely suspended in aqueous effluents, which is particularly relevant in wa.stewater treatment, the paper industry, etc.," - requires the use of water-soluble macromolecules, which arc mostly ionic in character and capable of interacting with the suspended material. With high-molecular-weight derivatives, the presence of a suitable content of ionogenic moieties as well as their uniform distribution along the polymeric chains are important in order to obtain the best performance of the flocculant, which should not completely cover the surface of the dispersed particles. 

The importance of water as a solvent has led to the development of water-soluble phosphines. This has been achieved by the incorporation of hydrophilic substituents into the phosphine stmcture. The choice of substituents, whether anionic, cationic, or neutral, depends on the exigencies of the end use. The anionic species [Ph2P(3-C6H4S03)l Na+ has been used to afford a water-soluble palladium catalyst (37) by Du Pont workers. ... 

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