Transition state mimick

Suzuki-Miyaura reactions with aryl bromides and triflates have been reported in the synthesis of plasmepsin I and II inhibitors using a hydroxyethylamine transition-state-mimicking scaffold [73], Four libraries of similar compounds were prepared where the Suzuki-Miyaura reaction was used for direct derivatization of the PI -position without protection of the hydroxyethylamine center. It was noted in this context that no epimerization occurred during the reaction and that exchange of cesium carbonate for sodium carbonate resulted in better yields (Scheme 15.33) [74]. 

Rosa M. D, Unge J, Motwani H. V, Rosenquist A, Vrang L, Wallberg H, Larhed M. Synthesis of PI -Functionalized Macrocyclic Transition-State Mimicking HtV-1 Protease Inhibitors Encompassing a Tertiary Alcohol, J. Med. Chem. 2014. p. 6444 -6457. DOI 10.1021/jm500434q... 

Bartlett has derived a method181 for proving that a putative transition state analog exerts its inhibitory power from successfully mimicking the transition state. If a series of structurally-related inhibitors (all containing the identical core chemical structure meant to simulate the transition state) bind to the target enzyme with log (fQ) values that linearly correlate (slope = 1) with the log (KMlkcai) values of the same series of structurally-related substrates, then... 

Transition states of this tetrahedral nature have now been mimicked effectively by a range of stable analogues, including phosphonic acids, phosphonate esters, a-difluoroketones, and hydroxymethylene functional groups (Jacobs, 1991). Lerner s group elicited antibodies to a tetrahedral anionic phosphonate hapten [3] (Appendix entry 2.9)2 whilst Schultz s group isolated a protein with high affinity for p-nitrophenyl cholyl phosphate [4] (Fig. 4) (Appendix entry 3.2). 

Selenoxide syn-eliminations are another reaction type favoured by less polar solvents (Reich, 1979). The planar 5-membered, pericyclic transition state for syn-elimination of [39] was mimicked by the racemic proline-based cis-hapten [39] to give 28 monoclonal antibodies (Appendix entry 8.5) (Zhou et al., 1997). Abzyme SZ-cts-42F7 converted substrate [40] exclusively into... 

Amide hydrolysis at alkaline pH involves a tetrahedral anionic intermediate, which was mimicked by the transition state analogue [49], an /V-aryl arylphosphonamidate, appropriately related to substrate anilide [50] (Fig. 18) (Appendix entry 2.8). 

GatCAB amidotransferase.This natural product mimics the charged 3 -terminus of aa-tRNA and has been used as a tool for the study of protein biosynthesis. The parent compound 22 is a very weak inhibitor of AdT. The amino acid chain is related to tyrosine and differs from the glutamic and aspartic side chains transformed in the kinase or the transamidase steps. Replacement of the methoxyphenyl moiety of puromycin by carboxylic acid derivatives (23-26) improved the ability to inhibit this AdT. Stable analogues of the transition state in the last step of the transamidation process (27-29) where the carbonyl to be attacked by NH3 is replaced by tetrahedral sulfur or phosphorus atom with a methyl group mimicking ammonia exhibited the highest activity. 

Such monomer interacts with a suitable p-di ketone forming an isolable enamide which effectively mimicks the transition state of the reaction. Copolymerisation of this adduct with the crosslinker and acrylamide followed by template removal yields small microgels (around 20 nm) that are able to catalyse the aldol condensation reaction about 19 times faster than nonimprinted controls. 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

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