Intermediates statins

Mareedu RK, Modhia FM, Kanin El, Linneman JG, Kitchner T, McCarty CA, Krauss RM, Wilke RA (2009) Use of an electronic medical record to characterize cases of intermediate statin-induced muscle toxicity. Prev Cardiol 12 88-94... 

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

It is worth noting here that inhibitors that interact with enzyme active site functionalities in ways that mimic the structure of covalent intermediates of catalysis can bind with very high affinity. This was seen in Chapter 1 with the example of statine-and hydroxyethylene-based inhibitors of aspartic proteases other examples of this inhibitor design strategy will be seen in subsequent chapters of this text. 

Greenberg, W.A., Varvak, A., Hanson, S.R. el ai (2005) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proceedings of the National Academy of Sciences of the United States of America, 101, 5788-5793. 

Bergeron, S., Chaplin, D.A., Edwards, J.H. et al. (2006) Nitrilase-catalyzed desymmetrization of 3-hydroxy-glutaronitrile preparation of a statin side-chain intermediate. Organic Process Research Development, 10, 661-665. 

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proc Natl Acad Sci USA 101 5788-5793... 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

Because HMG CoA reductase occurs before a branch point in the biosynthetic pathway, complete inhibition of the enzyme by cholesterol would necessarily deprive the cell of many other intermediates, some of which are important in cell growth and division. A group of drugs known as statins are widely used to reduce plasma cholesterol concentration by inhibiting HMG CoA reductase. Interest is now rising in the possible use of statins as anticancer drugs due to their impact on reducing the production of mediators of cell proliferation. 

Several approaches to statin side-chain intermediates have so far been discussed. Whereas these chemoenzymatic approaches provide clear benefits over the chemical processes, they do not harness the tme potential of biocatalysis as the biotransformations have simply been inserted into the existing chemical route. Wong and co-workers have developed a more biosynthetic-hke approach by using a mutant 2-deoxyiibose-5-phosphate aldolase (DERA)... 

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)... 

In summary, the results with pepsin extend the renin data reported by Szelke and Boger and strongly support the postulate of Boger that statine is an analog of a dipeptide tetrahedral intermediate.(20) The C-3 hydroxyl group hydrogen bonds to Asp-213 (220) and Asp-33(35) and displaces a "bound" water molecule from the active site. The isobutyl side chain of statine corresponds to the PI substituent that binds to the SI subsite on the enzyme. The C-1 and C-2 atoms of statine serve to span... 

The reduced risk of CHD achieved with the statins may also be due to drug actions independent of lowering blood cholesterol. Many important molecules besides cholesterol are generated by intermediates in the complex cholesterol synthesis pathway. These include the isoprenes geranylgeranyl and farnesyl, which are covalently attached to some proteins (isoprenylation) and target them to membranes where they function. The re-... 

The statin family of pharmaceuticals require a chiral side chain, representing a target that has attracted a great deal of activity focused on preparing various potential intermediates. A number of reports have been published on the reduction of chloroacetoacetate esters for conversion into this target molecule. A method suitable for large-scale production has been published that operates at 36.6gL and 95.2 % yield with 99% ee. This reaction is shown in Figure 1.43. 

Afifymax s thiolacyl library (Fig. 1.9) and Pharmacopeia s statine library (Fig. 1.10) are pharmacophore-based libraries however, their design is different. In the former library, a pool of advanced library intermediates are derivatized with the pharmacophore (thiolacylation) as the final step in library construction, while in the latter library the pharmacophore (statine) is derivatized with synthons as part of library construction. 

These may mimic the tetrahedral intermediate more closely than statine or hydroxyethylene analogs. 

Deoxy-D-Ribose 5-Phosphate Aldolase (DERAj-Based Routes to Statin Intermediates 1131... 

For the synthesis of atorvastatin we developed an efficient process that allows for direct cyanation of lactone 2 [21] to cyanomethyl lactone 3 to finally afford the well known atorvastatin precursor 5 (Scheme 6.3) [22]. It is worth pointing out that the two synthetic routes to the advanced statin intermediates 5 and 6 described here avoid ultra-low temperature chemistry, heavy metal catalysts, metal-organic species, and chromatographic purification steps. The DERA-catalyzed chemistry to form the six-carbon chiral unit is cost competitive and operated on a commercial scale. 

To overcome problems of poor acceptor substrate acceptance, high concentrations of aldehyde substrates are required to obtain synthetically useful product yields. Unfortunately, DERA shows rather poor resistance to such high aldehyde concentrations, especially toward CIAA, resulting in rapid, irreversible inactivation of the enzyme. Therefore, the organic synthesis of (3R,5S)-6-chloro-2,4,6-trideoxy-hexapyranoside 1 requires very high amounts of DERA. Thus, despite the synthetic usefulness of DERA to produce chiral intermediates for statin side chains, the large-scale application is seriously hampered by its poor stability at industrially relevant aldehyde concentrations. The production capacity for such 2,4,6-trideoxy-hexoses of wild-type E. coli DERA is rather low [15]. 

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