Silanediol inhibitors of angiotensin-converting enzyme. Synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analogues

Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl 3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second stereogenic center. The diastereomeric identities were established by X-ray crystallography of an intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC(50) = 3.8-207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC(50) = 1.0-46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC(50) = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC(50) = 72 nM), suggesting an alternative mode of binding to the enzyme.     

Efficient asymmetric synthesis of silanediol precursors from 1,5-dihydrosiloles

Dihydrosiloles are easily prepared from 1,3-dienes and dichlorosilanes, even on kilogram scale. Asymmetric hydroboration of a 3-alkyl-1,5-dihydrosilole, prepared from a 2-alkyl-1,3-diene, followed by treatment with aqueous HF results in Peterson fragmentation, forming optically active 3-alkyl-4-fluorosilyl-1-butenes. The fluorosilanes are stable to moisture but very reactive toward nucleophiles. In addition, they can be converted to nucleophilic silyllithium reagents.     

Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease

BACKGROUND: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. RESULTS: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. CONCLUSIONS: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.     

Enantioselective alpha-silyl amino acid synthesis by reverse-aza-Brook rearrangement

[reaction: see text] Asymmetric reverse-aza-Brook rearrangement of N-Boc-N-trialkylsilyl allylamine yields an enantiomerically enriched alpha-amino allylsilane. Oxidative cleavage of the alkene leads to a Boc-protected amino acid with the configuration of naturally occurring amino acids (L). Standard coupling protocols, including the use of trifluoroacetic acid for removal of the Boc group, yield a tripeptide with a central silane amino acid.     

Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme

Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu-[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]-Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu-[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC(50) values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC(50) values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.     

An enolate-accelerated cope rearrangement

The first example of an enolate accelerated Cope rearrangement is described along with its importance in the rearrangement of 5-alkoxy-deca-1,3,7,9-tetraenes.     

Asymmetric synthesis of alpha-amino allyl,benzyl, and propargyl silanes by metalation and rearrangement

[reaction: see text] Metalation of a Boc-protected N-silylamine alpha to nitrogen results in migration of the silicon from nitrogen to carbon (reverse aza-Brook rearrangement), yielding an alpha-amino silane. The Boc group acts initially as a metalation-directing group and then to stabilize the nitrogen anion, providing a driving force for the rearrangement. In the presence of (-)-sparteine, the new chiral center is formed in >90% ee from allyl, benzyl, and propargylamines.     

Transform-Limited Pulses Are Not Optimal for Resonant Multiphoton Transitions

Maximizing nonlinear light-matter interactions is a primary motive for compressing laser pulses to achieve ultrashort transform limited pulses. Here we show how, by appropriately shaping the pulses, resonant multiphoton transitions can be enhanced significantly beyond the level achieved by maximizing the pulse's peak intensity. We demonstrate the counterintuitive nature of this effect with an experiment in a resonant two-photon absorption, in which, by selectively removing certain spectral bands, the peak intensity of the pulse is reduced by a factor of 40, yet the absorption rate is doubled. Furthermore, by suitably designing the spectral phase of the pulse, we increase the absorption rate by a factor of 7.