Isosteric replacements

Furthermore, the GPO procedure can also be used for a preparative synthesis of the corresponding phosphorothioate (37), phosphoramidate (38), and methylene phosphonate (39) analogs of (25) (Figure 10.20) from suitable diol precursors [106] to be used as aldolase substrates [102]. In fact, such isosteric replacements of the phosphate ester oxygen were found to be tolerable by a number of class I and class II aldolases, and only some specific enzymes failed to accept the less polar phosphonate (39) [107]. Thus, sugar phosphonates (e.g. (71)/(72)) that mimic metabolic intermediates but are hydrolytically stable to phosphatase degradation can be rapidly synthesized (Figure 10.28). 

Among the strategies used for the development of GST Pl-1 inhibitors is the modification of the GSH backbone to leverage its inherent affinity for GST Pl-1. One approach centered on the incorporation of a carbamate group as an isosteric replacement of the y-carboxylic Glu linkage in GSH. Synthesis and in vitro testing of 42 and 43 showed that this carbamate-replacement approach was not well tolerated [67]. 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

P. Cieplak, P.A. Kollman, Peptide mimetics as enzyme inhibitors Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor, J. Comput. Aided Mol. Des. 7 (1993) 291-304. 

The simplest approach to isosteric replacement of one or both sulfur atoms of the cystine disulfide with a methylene or ethylene moiety is given for natural bioactive peptides when one cysteine residue is located in the N-terminal sequence position and the related amino group or peptide extension is not involved in the bioactivity. This allows for direct side chain to backbone (N-terminus) cyclization via amide bonds with suitable 5-carboxyalkyl derivatives of the second cysteine residue, or with the oo-carboxy group of aminodicarboxylic adds containing an alkyl side chain that mimics the Ca to Ca spacer in cystine. Thereby, the length and degree of branching of the sulfide or alkyl spacer can additionally be varied. 

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) ... 

Isosteric replacement with fluorine is an effective way to decrease the carcinogenicity of polyaromatic hydrocarbons. For example, 7-methylbenz[o]anthra-cene is highly carcinogenic, but the 1-fluoro analog is not, as the presence of fluoride prevents CYP epoxi-dation at the 1,2-position. 

Isosteric replacement of the thiourea moiety with the cyanoguanidine moiety gave cimetidine (39), a potent H2-receptor antagonist that lacks the toxicity of 38. Cimet-idine is a widely used anti-ulcer medication because of its effectiveness in treating ulcers and relative safety. It is noteworthy that in this example, this isosteric modification selectively reduced toxicity without affecting pharmacological activity. 

As for the design of safer drug substances, isosteric substitution has been used for many years for the design of safer pesticide substances, although to a lesser extent. Isosteric replacement of carbon with silicon, for example, has resulted in a number of safe but effective pesticides [76]. An example of the use of isosteric substitution of carbon with silicon in the design of safer a pesticide is in the case of the insecticide MTI-800 (40) and its much less toxic silane isostere, 41. 

Based on the examples provided above and the many successful applications of isosterism in the design of safer drugs and pesticides, it appears that isosteric replacement should have an expanded role in the design of safer commercial chemicals, especially since isosteric substitution has the added marketing advantage that it may enable one to circumvent chemicals protected by patents and marketed by competitors. 

This has been found to be the case with valproic acid (2-propylpentanoic acid) (12), which is hepatotoxic, and 2-fluorovalproic add (22), which is much less hepatotoxic, discussed in Sedion 4.3.1. The hepatoxidty of 12 involves cytochrome P450 abstraction of its C-2 hydrogen atom. The C-2 fluorine atom of 22 cannot be removed by cytochrome P450 metabolism. It would be interesting to observe if the same isosteric replacement would reduce the hepatoxidty of other carboxylic acids, such as the widely used 2-ethylhexanoic add. 

Sieburth S.Mc.N., (1996) Isosteric replacement of carbon with silicon in the design of safer chemicals, in Designing Safer Chemicals Green Chemistry for Pollution Prevention. ACS Symposium Series vol. 640 (eds S.C., DeVito and R.L. Garrett) American Chemical Society, Washington, DC, pp. 74—83. 

Sieburth, S.McN., Manly, C.J. and Gammon, D.W. (1990) Organosilane insecticides. Part I. Biological and physical effects of isosteric replacement of silicon for carbon in etofenprox... 

Products), 1998a 1999) has described analogs of sulindac that act as selective COX-2 inhibitors, where a tetronic acid moiety is used as an isosteric replacement for the carboxylic acid group (Jimenez et al., 2000). 

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Scheme 21 Isosteric Replacement of a ds-Amide Bond with a 1,5-Substituted Tetrazolel115-1181...

Representatives of all kinds have been explored for synthetic applications while mechanistic investigations were mainly focussed on the distinct FruA enzymes isolated from rabbit muscle [196] and yeast [197,198]. For mechanistic reasons, all DHAP aldolases appear to be highly specific for the donor component DHAP [199], and only a few isosteric replacements of the ester oxygen for sulfur (46), nitrogen (47), or methylene carbon (48) were found to be tolerable in preparative experiments (Fig. 7) [200,201], Earlier assay results [202] that had indicated activity also for a racemic methyl-branched DHAP analog 53 are now considered to be artefactual [203]. Dihydroxyacetone sulfate 50 has been shown to be covalently bound via Schiff base formation, but apparently no a-deprotonation occurred as neither H/D-exchange nor C-C... 

Solution-state NMR studies suggest that the catalysts containing l- and D-Pro adopt p-turns and p-hairpins in solution,respectively. Reactions exhibit first-order dependence on catalyst 24, consistent with a monomeric catalyst in the ratedetermining step of the reaction. These catalysts exhibit enantiospecific rate acceleration, in comparison to the reaction rate when NMI is employed as catalyst. An isosteric replacement of an alkene for a backbone amide in a tetrapeptide catalyst (catalysts 32 and 33, Fig. 4) has lent credence to a proposed mechanism of rate acceleration [31). While catalyst 32 exhibits a fcrei=28 with substrate 27, alkene-containing catalyst 33 is not selective in this kinetic resolution and also affords a reduced reaction rate. This suggests that the prolyl amide is kinetically significant in the stereochemistry-determining step of the reaction. 

Cyclopropane compounds containing the olefin isostere replacement for the amide bond were prepared using Julia olefination chemistry. Aldehydes 39 and 40 were obtained by LAAIH4 reduction of the chiral w-butyl esters of 32 and 33, respectively, followed by swera oxidation of the corresponding alcohols (Figure 22). Condensation of the (S)-N-BOC-cyclohexylalanine sulfone 41 with aldehyde 39 gave after treatment with 2% Na(Hg) and deprotection, the trans and cis olefin-amines... 

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

Prostacyclin (11.53) is a signal molecule in the body that inhibits clotting and acts as a vasodilator. Prostacyclin is unstable and has an extremely short half-life (Figure 11.10). The instability of prostacyclin in the body is primarily attributed to its enol ether functionality, which readily undergoes hydrolysis. Isosteric replacement of the ring oxygen with a CH2 group and small modifications of the side chain afforded iloprost (Ilomedine, 11.54), an FDA-approved treatment for certain... 

Figure 4.4 Examples of drugs discovered by isosteric replacement...

In a first round, we tried to obtain, through structural variation of known active molecules,. new and superior biological effects. We were particularly interested to check the consequences of the isosteric replacement of structural elements in chlorophenyl derivatives as shown above. 

Isosteric replacement of phenyl, that is, replacement of phenyl by other aromatic groups of similar size such as furyl, pyridyl, and thienyl, is generally disadvantageous in analgesics (the thiambutenes are a special exception, p. 310). Thus, the 2-thienyl analogs of pethidine(65) and its seven-membered ring... 

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