Highly diastereoselective alkylations of chiral amide enolates: new routes to hydroxyethylene dipeptide isostere inhibitors of HIV-1 protease

Askin, David; Wallace, Michael A.; Vacca, Joseph P.; Reamer, Robert A.; Volante, R. P.; Shinkai, I.

doi:10.1021/jo00036a004

Cited by 129 publications

(26 citation statements)

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“…PME was synthesized by methylation of pepstatin A. The synthesis of L685,458 was based on a compilation of previously published procedures (27)(28)(29). Compounds 1 and 2 were synthesized using a procedure similar to the one reported in the international patent publication by Smith et al (25).…”

Section: Methodsmentioning

confidence: 99%

Linear Non-competitive Inhibition of Solubilized Human γ-Secretase by Pepstatin A Methylester, L685458, Sulfonamides, and Benzodiazepines

Tian

Sobotka-Briner

Zysk

et al. 2002

Journal of Biological Chemistry

149

139

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Cerebral deposition of amyloid ␤-protein (A␤) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because A␤ is produced from the processing of amyloid ␤-protein precursor (APP) by ␤-and ␥-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike ␤-secretase, which is a monomeric aspartyl protease, ␥-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of ␥-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting ␥-secretase may be an aspartyl protease. However, the mechanism of inhibition of ␥-secretase by pepstatin and L685458 has not been elucidated. In this study, we report that pepstatin A methylester and L685458 unexpectedly displayed linear non-competitive inhibition of ␥-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of ␥-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed. Accumulation and deposition of ␤-amyloid (A␤)1 peptides in the cerebral cortex is believed to be an early and central process in the pathogenesis of Alzheimer's disease. The A␤ peptides are generated from sequential proteolytic cleavage of the amyloid precursor protein (APP) by ␤-and ␥-secretases, which are therefore considered important targets for therapeutic intervention. Molecular cloning (1-3) and crystallographic studies (4) have unequivocally established ␤-secretase as an aspartyl protease. However, the identity of ␥-secretase remains elusive.It is known that transmembrane proteins presenilin 1 (PS1) and presenilin 2 (PS2) are essential for intramembranous proteolytic ␥-cleavage of APP (5) and a few other ␥-secretase substrates such as Notch (6 -9) and ErbB4 (10). Evidence suggests that presenilins may have direct catalytic activity (11, 12), but recent reports indicate that this activity requires interactions between presenilins and other proteins such as nicastrin (13) and co-fractionates with a very high molecular weight complex (14). Mature presenilins themselves form subunit heterodimers between the N-and C-terminal fragments, which are generated from endoproteolytic cleavage of the full-length presenilin (15, 16). This complex membrane-bound molecular organization has hindered efforts to purify and reconstitute ␥-secretase activity.In the absence of purified enzyme and crystal structures, inhibition studies have played a prominent role in the understanding of the nature of ␥-secretase. ␥-secretase activity is sensitive to aspartyl protease transition state analogs such as the hydroxyl ethylene isosteres, pepstatin (17-19) and L685458 (20), typical aspartyl protease transition state inhibitors. Peptidomimetics containing a dif...

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Section: Methodsmentioning

confidence: 99%

Linear Non-competitive Inhibition of Solubilized Human γ-Secretase by Pepstatin A Methylester, L685458, Sulfonamides, and Benzodiazepines

Tian

Sobotka-Briner

Zysk

et al. 2002

Journal of Biological Chemistry

149

139

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“…The same reversal is found in the reaction of the amide enolate 103 218 . By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the lithium enolate 104 with the chiral oxiranes 105 219 and 106 220 . It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselectivities can be achieved.…”

Section: Lithium Enolates and Related Compoundsmentioning

confidence: 84%

Reactivity of Oxiranes with Organolithium Reagents

Chemla

Vrancken

2009

Patai's Chemistry of Functional Groups

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“…Functionalized -lactones have attracted considerable attention because of their importance as building blocks in the synthesis of a number of natural products and biologically relevant compounds (Samarat et al, 2001), for example, precursors of inhibitors of HIV-1 protease (Askin, et al, 1992). We have synthesized the title compound, (I), by the reaction of -butyrolactone and 4-chlorobenzaldehyde.…”

Section: Commentmentioning

confidence: 99%