Ground-state analog

Bartlett etal. [14] described the synthesis of a series of fluoroolefin tripeptide isosteres Cbz-Glyi/r[(Z)-CF=CH]LeuXaa (Xaa = Gly, Ala, Leu, Phe, and NH2) (10) (Scheme 3) as the ground-state analog inhibitors of thermolysin. Treatment of acid (15) with ammonia gave 10e. The inhibitors 10a-d are formed by conventional amide acid coupling reactions of suitably protected amino acids followed by saponification with lithium hydroxide. 

P.A. Bartlett, A. Otake, Fluoroalkenes as peptide isosteres Ground state analog inhibitors of thermolysin, J. Org. Chem. 60 (1995) 3107-3111. 

Steps 4-6 describe the evolution of the system when the solute returns to the ground state. For Step 4 and 5 we introduce the ground state analog of the time dependent energy function (7-43) as ... 

A series of constrained ground-state analogs of a cis-Gly/Ala-Pro dipeptide (i.e. compound 10) displayed micromolar affinities for hCypl8, but the exact mode of interaction with the PPIase is not clear, although fluorescence intensity enhancement at 350 nm strongly suggests the existence of an interaction with the S2 -S3 subsite. However, no data regarding an inhibition of the enzymatic activity were reported [192]. 

There are problems with this eloquent concept, however. A transition-state analog, as a matter of practicality, must be a stable compound. At best it can only resemble the unstable segment of the substrate s actual transition state since that latter s instability is due to partially formed (and unformed) covalent bonds. Our best hope is the development of relatively crude analogs that may nevertheless be superior in affinity to the substrate s ground-state analogs, and yet result in highly effective reversible inhibitors. 

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