Strategies carboxyl replacement

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

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]. 

Another strategy for catalyzing the hydrolysis of an ester or an amide is to replace water by a stronger nucleophilic group that is part of the enzyme s active site. The HOCH2— group of a serine residue is often used in this way. In such cases, the reaction of the serine with the substrate splits the overall reaction into a two-step process. Instead of immediately yielding the free carboxylic acid, the breakdown of the initial tetrahedral intermediate yields an intermediate ester that is attached covalently to the enzyme. 

Strategy To identify the carboxylic acid chloride used in the Friedel-Crafts acylation of benzene, break the bond between benzene and the ketone carbon and replace it with a -Cl. 

Replacement of Pro5 by its sulfur analog, thiazolidine-4-carboxylate (Thz), a strategy that led to enhanced activities in oxytocin derivatives, yielded the potent peptide [D-Met2, Thz5]-enkephalinamide, 4 to 5 times as potent as morphine (MTF, iv)/91 ... 

Strategy A. nucleophilic acyl substitution involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Strategy Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative—either an amide (Hofmann) or an acid chloride (Curtius)—into a primary amine with loss of one carbon, RCOY — RNH. Both reactions begin with the same carboxylic acid, which can be identified by replacing the -NH2 group of the amine product by a -COOH group. In the present instance, o-methylphenylacetic acid is needed. 

An illustration of the second strategy is provided by the para-cyano analogs of the non-nutritive sweetener suosan (Figure 41.18). The replacement of the planar carboxylic group by the bioisosteric tetrazolyl group yields less potent, but still sweet compounds. ... 

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