Valency, isosterism

The concept of isosterism 481 has been used in medicinal chemistry. Molecules or groups which possess physicochemical similarity (e.g., similarity in size or the number of valence electrons) are called isosteres. The classical isosteres include, for instance, the following two pairs of groups ... 

The isosteric replacement of atoms or gronps in a molecule is widely nsed in the design of antimetabolites or drngs that alter metabolic processes. Isosteric gronps, according to Erlenmeyer s definition, are isoelectronic in their outermost electron shell. However, since their size and polarity may vary, the term isostere is somewhat misleading. Isosteres are classified according to their valence (i.e., the number of electrons in the onter shell) ... 

Isosteres Molecules or ions of similar size and the same number of valence electrons... 

Although fluorine does not have the same valency as hydrogen, it is often considered an isostere of that atom since it is virtually the same size. Replacement of a hydrogen atom with a fluorine atom will therefore have little steric effect, but since the fluorine is strongly electronegative, the electronic effect may be dramatic. 

The assumption of resemblance reveals a second, subtler, presupposition. The periodic chart places elements in columns, or groups, based on the numbers of their valence electrons. Thus, nitrogen is placed in group 5 (15 in the IUPAC scheme) even though it frequently expresses a valence of three. Fixed-period molecules with the same total number of atomic valence-shell electrons ( isoelectronic, horizontally isoelectronic, or isosteric molecules such as N2 and CO) usually have properties more similar than do molecules selected at random. Molecules whose atoms come from different periods but have the same numbers of valence electrons ( vertically isoelectronic or isovalenf molecules such as the salts LiF, Nal, and CsCl), often have somewhat similar properties. So, the sum of the atomic valence electron counts, i.e., the sum of the atomic group numbers, is important. Thus, it appears that using... 

Bioisosteric interchanges, of course, are not limited to univalent functions. In fact, divalent atoms and groups add the additional factor of steric similarity to the equation since the bond angles between the valencies are very similar. The angles for/CH2 (l 11.5°),/NHv(l 11°) /S (l 12°), and/Q(108°) illustrate this point. When a deviation of 3 degrees, depending on the full structural features of the compound, are taken into consideration, it becomes apparent how identical these features can be. A rather convincing example is seen when the bioactivity relationship between the isosteric ester and amide moieties is examined (Fig. 1-4). 

The concept of isosterism was later broadened by Erlenmeyer in 1932 to include elements, ions, or molecules with the same number of electrons at the valence level (Table 2.3) [3]. Erlenmeyer stated that elements in the same column of the periodic table are isosteres among themselves and also introduced the concept of electronically equivalent rings. 

Although isoelectronic and isosteric relationships are usually attributed to Langmuir, they were extended by Grim and Erlenmeyer. Grimm [121-123] considered all molecules with the same number of valence electrons regardless of the number of atoms involved and used isomorphism as a criterion. Erlenmeyer concluded that only the outer number of electrons should be counted in proposing iso-sterism and applied it widely to organic molecules [124],... 

Langmuir I (1919) Isomorphism, isosterism and covalence. J Am Chem Soc 41 1543-1559 Langmuir I (1920) The octet theory of valence and its applications with special reference to organic nitrogen compounds. J Am Chem Soc 42 274-292... 

Stmctural modifications of the mescaline-tyjte 3,4,5-substitution pattern revealed a particular influence of the para (position 4) on human psychoactivity. Potency appears to increase with an increase in alkyl chain length attached to the oxygen at this position but then drops beyond a chain length of three atoms. A tenfold increase in potency over mescaline has been observed with 4-allyloxy-3,5-trimeth-oxyphenylethylamine (AL). Thiomescaline represents an example of isosterism where oxygen has been replaced by sulphur that has the same valency. This modification also displayed a tenfold increase in potency when compared with mescaline. An extended duration of action of 10-15 hours has been reported for thiomescaline. 

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