Molecular modifications

C W 1979. Isosterism and Molecular Modification in Drug Design. Chemical Society Reviews 53-580. 

Elucidation of the stmctural requirements for dmg interaction at the recognition site is by the study of stmcture—activity relationships (SAR), in which, according to a specific biologic response, the effects of systematic molecular modification of a parent dmg stmcture are determined. Such studies have permitted the classification of discrete classes of pharmacological receptors. For example, the neurotransmitter acetylcholine acts at both peripheral and central receptors which are of at least three distinct types. The effects of acetylcholine are mimicked in smooth and cardiac muscles and secretory... 

The natural prostanoids have myriad biological effects and held great promise as potential therapeutic agents in numerous diseases. The natural prostanoids, however, also have three notable drawbacks which medicinal chemists have tried to overcome by molecular modification in order to produce acceptable dmg candidates. These drawbacks are rapid metaboHsm which results in lack of activity if taken orally and a short duration of action, numerous side effects due to their multiplicity of biological activities, and poor chemical stabiUty, a characteristic especially pronounced in PGE, -D, and -I stmctures. 

Tricyclic Antidepressants. Imipramine [50-49-7] (32), which was the first tricycHc antidepressant to be developed, is one of many useful psychoactive compounds derived from systematic molecular modifications of the antihistamine prometha2ine [60-87-7] (see Histamine and histamine antagonists). The sulfur atom of prometha2ine was replaced with an ethylene bridge and the dimethylamino group attached to an / -propyl group, rather than to an isopropyl one, of the side chain. The actual synthesis of (32) is typical of the compounds in this class (37). 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

As with other rigid amorphous thermoplastic polymers such as PVC and polystyrene (see the next chapter) poly(methyl methacrylate) is somewhat brittle and, as with PVC and polystrene, efforts have been made to improve the toughness by molecular modification. Two main approaches have been used, both of which have achieved a measure of success. They are copolymerisation of methyl methacrylate with a second monomer and the blending of poly(methyl methacrylate) with a rubber. The latter approach may also involve some graft copolymerisation. 

Other more exotic types of calamitic liquid crystal molecules include those having chiral components. This molecular modification leads to the formation of chiral nematic phases in which the director adopts a natural helical twist which may range from sub-micron to macroscopic length scales. Chirality coupled with smectic ordering may also lead to the formation of ferroelectric phases [20]. 

To date, only two exceptions to the pK of 8 rule have been found the Rieske protein from Sulfolobus acidocaldarius (139) and that from Thiobacillus ferrooxidans (140). In both cases, a first pK is observed in the vicinity of 6 (Fig. 7). The fact that Sulfolobus and Thiobacillus are phylogenetically almost as distant as they can possibly be, but share acidophilic growth conditions (medium-pH of 2), indicates that the pK, which is lower by 2 pH units in Sulfolobus and Thiobacillus, reflects adaptation. In the absence of structural information for the two acidophilic Rieske proteins, the molecular modifications resulting in this pK shift are difficult to guess. The absence of sequence data for the Thiobacillus protein furthermore precludes a comparative approach. It seems likely, however, that the solvent-exposed histidine ligands to the cluster will become slightly more bur-... 

Each of the individual ADME components can be used independently or together to evaluate the influence of molecular modifications on hazard reduction. 

Fig. 59. Molecular modification of semiconductor silicon surfaces. Removal of the oxide generates a hydrogen-terminated layer that reacts with a range of molecular functional groups including alkenes. 

For solid nitrogen five modifications are known that differ in the packing of the N2 molecules. Two of them are stable at normal pressure (transition temperature 35.6 K) the others exists only under high pressure. At pressures around 100 GPa a phase transition with a marked hysteresis takes place, resulting in a non-molecular modification. It presumably corresponds to the a-arsenic type. Electrical conductivity sets in at 140 GPa. 

The most common of all natural polymers is cellulose. It is ubiquitous in plant life in various molecular modifications and structural arrangements. Large quantities are found in the trunks, branches and leaves of trees as well as in... 

A great deal of structural modification work has ensued in the subsequent years. At present, however, the level of effort and number of laboratories involved in this area are small compared to that during the 1960s and 1970s, when hallucinogens were a popular topic in the lay media. It will be easiest to describe this work by focusing on specific types of molecular modifications and how they affect activity. 

In summary, it may be said that theoretical calculations, both ab initio and semiempirical, are not yet feasible, as they are too coarse a tool for the quantitative interpretation of subtle changes in carbon shieldings caused by slight molecular modifications, at least for aliphatic compounds. Nevertheless, they... 

Energy level diagrams have seldom been used to show how the disposition of levels changes with variations of the a and j8 parameters describing the system, and how such processes can be related to spectroscopic changes and postulated reaction mechanisms. Yet, they can often give a qualitative understanding of the effects of molecular modifications with a minimum of effort, and for this reason at least deserve mention. 

In most cases, a suitable molecular modification of the catalyst structure is required to obtain the desired thermoresponsive properties. Polyether and in particular PEG substituents are receiving considerable interest in this field. The present study has addressed structure-activity relationships for well-defined low molecular weight model ligands in the rhodiiun-catalyzed hydroformylation of 1-octene as benchmark reaction. Figure 3 summarizes the observed trends. 

This initial discovery has since led, by appropriate molecular modifications, to the synthesis of three compounds currently in advanced testing. 

Since the discovery in 1973 of metal-like conductivity in the charge transfer salt tetrathiafulvalene-tetracyano-p-quinodimethane (TTF-TCNQ, 1,-2), a host of new materials have been prepared displaying this interesting property. Widespread research on these materials has led to an improved understanding of the physics underlying the organic metallic state, and to a succession of molecular modifications which have enhanced these properties. ... 

Most glucocorticoids have some mineralocorticoid effect, which is usually considered an undesirable activity. Through structural chemistry and structure-activity relationship (SAR) studies, molecular modifications can separate the two activities. 

The structure-activity relationships of glucocorticoids are based on two natural hormones, cortisol (3.8) and corticosterone (5.61). The characteristic structural features of these hormones are the conjugated 3-ketone, the 11-OH group, and the up-ketol side chain. Molecular modifications have been aimed at deriving compounds with glucocorticoid... 

Molecular modifications in the form of simplifications of the morphine ring system have been undertaken for many years, and have resulted in the development of some spectacularly successful compounds devoid of addictive properties. 

Semisynthetic Penicillins. However useful they may be, natural penicillins have several drawbacks. They have a relatively narrow activity spectrum, primarily inhibiting Gram-positive bacteria only. They are acid- and lactamase-sensitive, and in a small percentage of patients they cause allergie side effects. All of these limitations could potentially be overcome by molecular modifications during the biosynthesis of these drugs. Unfortunately, however, the fermentation process used in penicillin production is not very flexible and does not permit the incorporation of very many amide side chains into the molecule. 

Reducing the dimensionality of the descriptor space not only facilitates model building with molecular descriptors but also makes data visualization and identification of key variables in various models possible. Notice that while a low dimension mathematically simplifies a problem such as model development or data visualization, it is usually more difficult to correlate trends directly with physical descriptors, and hence the data become less interpretable, after the dimension transformation. Trends directly linked with physical descriptors provide simple guidance for molecular modifications during potency/property optimizations. 

---