Transition-state analog

B. S. Green, Y. Ashani, and D. Chipman, eds.. Chemical Approaches to Understanding En me Catalysis Biomimetic Chemistry and Transition State Analogs, Elsevier, Amsterdam, 1982. 

In summary, structural studies of Ras and Gq with GTP-yS and a transition state analog have illuminated the catalytic mechanism of their GTPase activity, as well as the mechanism by which GTP hydrolysis is stimulated by GAP and RGS. In addition, these structural studies have shown how tumor-causing mutations affect the function of Ras and Gq. 

Transition-State Analogs Bind Very Tightly to the Aetive Site... 

It should be noted that transition-state analogs are only approximations of the transition state itself and will never bind as tightly as would be expected for the true transition state. These analogs are, after all, stable molecules and cannot be expected to resemble a true transition state too closely. 

X-ray crystallographic studies of serine protease complexes with transition-state analogs have shown how chymotrypsin stabilizes the tetrahedral oxyanion transition states (structures (c) and (g) in Figure 16.24) of the protease reaction. The amide nitrogens of Ser and Gly form an oxyanion hole in which the substrate carbonyl oxygen is hydrogen-bonded to the amide N-H groups. 

Transition-State Stabilization and Transition-State Analogs... 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

It is noteworthy that reaction diastereoselectivity closely parallels the isomeric purity of the allyiboronates, thus underscoring the requirement that the method of reagent synthesis be highly stereoselective. The data presented in Table 1 also provide strong evidence for the involvement of chair-like, cyclic transition states, analogous to the transition states previously invoked for aldol reactions46. 

It is argued that the poor diastereoselectiyity in the reactions of the (Z)-l-methyl-2-butenyl-boronate reflects the competition for placement of R versus methyl in an axial position in transition states analogous to 6. 

Several studies of reactions of configurationally unstable a-substituted allylboranes have also been reported19,29. The reactions of dialkyl[( )-l-alkyl-2-butenyl]boranes and aldehydes at — 78 °C provide a mixture of syn- and an/i -diastereomers. reflecting reactions by both the Z-and /f-isomers. When generated and used at — I00°C, however, the ff/m-diastereomer is obtained with >95% diastercoselectivity and >90% selectivity for the /T-olefin isomer by way of a transition state analogous to 429. This result suggests that the allylboron isomerization is slow at —100 JC relative to carbonyl addition. 

The reaction is believed to proceed via a six-membered cyclic transition state, analogously to the carbonyl addition of enolates, but the energy differences between boat- and chair-like arrangements are lower for x-sulfinyl carbanions69. Tor tert-butyl sulfoxides only anti- and, vn-products are obtained, arising from the approach onto the same diastereotopic face of the anion, but with different relative topicity. The exchange of lithium by zinc causes an increase of the anft-produci, but attempts to titanate the anion failed (see Table 3)69. 

Blackburn G. M., Kingsbury G., Jayaweera S., Burton D. R. Expanded Transition State Analogs Ciba Found. Symp. 1991 159 211-226... 

Figure 3.2 Transition state analog principle for the design of catalytic antibodies.

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

Wolfenden, R. Transition state analogs and enzyme catalysis. Ann. Rev. Biophys. Bioeng. 1976, 5, 271-306. 

Basmadjian G., Singh S., Sastrodjojo B. et al. Generation of polyclonal catalytic antibodies against cocaine using transition state analogs of cocaine conjugated to diphtheria toxoid. Chem. Pharm. Bull. 43 1902, 1995. 

Strain and Distortion Transition-State Stabilization Transition-State Analogs Chemical Catalysis... 

TRANSITION-STATE ANALOGS are stable molecules that are designed to look more like the transition state than like the substrate or product. Transition-state analogs usually bind to the enzyme they re designed to inhibit much more tightly (by 1000-fold or more) than the substrate does. 

Different oxidation states of sulfur have also been explored, particularly sulf-ones and sulfonamides as transition state analogs of lysine deacetylation, but without much success. The monodentate SAHA-like methyl sulfoxide 7 proved most potent, but still with an enzyme IC50 of only 48 pM and indications of HDAC/TDAC selectivity in cellular assays [28]. 

Yliniemela, A., Konschin, H., Neagu, C., Pajunen, A., Hase, T., Brunow, G. and Teleman, 0. Design and synsthesis of a transition state analog for the ene reaction between maleimide and l-alkenes, JAm.Chem.Soc., 117(1995), 5120-5126... 

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