Scott McN. Sieburth

Silanediols: A New Class of Potent Protease Inhibitors

Transition state analogues of the peptide hydrolysis intermediate can take the form of complex silanediols such as 1, which inhibits angiotensin-converting enzyme (ACE) at nanomolar concentrations. In contrast, earlier investigation of enzyme inhibition with simple silanediols and silanetriols showed them to be inactive.

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 molecules 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.

Macroexpansion methodology : Medium ring synthesis based on an eight unit ring expansion process

Abstract Treatment of 1,2-( E,E )-di(1-buta-1,3-dienyl)cyclohexanol ( 21 ) with potassium hydride in tetrahydrofuran at room temperature resulted in the facile formation of a 14 -membered ring dienolate which on kinetic protonation provided cyclotetradeca-3,5,7-trien-1-one. This novel rearrangement which provides the basis for an efficient, eight unit ring expansion method was also observed when 5,8-dimethyl-5-hydroxy-1,3,7,9-decapentaene ( 28 ), the acyclic analogue of 21 , was treated with potassium hydride in tetrahydrofuran. Methodology for the preparation of 21 and 28 including the preparation of 1-lithio-1,3-butadiene is also described.

Efficient, Enantioselective Assembly of Silanediol Protease Inhibitors

A five-step assembly of silicon-protected dipeptide mimics from commercially available reagents is described. This methodology makes silanediol protease inhibitors readily available for the first time. The sequence features asymmetric hydrosilylation, a novel reduction of a silyl ether to a silyllithium reagent, and addition of this dianion to a sulfinimine, to produce the complete inhibitor skeleton with full control of stereochemistry. Oxidation of the primary alcohol to an acid completes the synthesis.

Silanediol-Based inhibitor of thermolysin ☆

The first silanediol inhibitor of thermolysin is reported, prepared by analogy with the Grobelny/Bartlett phosphinate inhibitor. A Cbz group on nitrogen proved to be unstable to the triflic acid mediated silanediol deprotection and was replaced with a dihydrocinnamoyl group. The silanediol was prepared in high purity by hydrolysis of a difluorosilane intermediate and proved to be an effective inhibitor, differing from the phosphinate by a factor of 4 (K(i)=41nM).

Serine Protease Inhibition by a Silanediol Peptidomimetic

Silanediol peptidomimetics are demonstrated to inhibit a serine protease. Asymmetric synthesis of the inhibitor was accomplished using Brown hydroboration and CBS reduction of an acylsilane intermediate. The silanediol product was found to inhibit the serine protease chymotrypsin with a K(i) of 107 nM. Inhibition of the enzyme may involve exchange of a silane hydroxyl with the active site serine nucleophile, contrasting with previous silanediol protease inhibitors.

Synthesis and properties of a sterically unencumbered δ-silanediol amino acid.

An amino acid carrying a 1-(4-dihydroxymethylsilyl)butyl side chain has been prepared in enantiomerically pure form as a potential inhibitor of the enzyme arginase, a pharmaceutical target. As a water-soluble silanediol, this compound was anticipated to be entropically stabilized against polymerization and siloxane formation. At 50 mM in D(2)O, the degree of oligomerization was found to be pH dependent, with diastereomeric mixtures formed on condensation. Above pH 11 the silane is largely monomeric.

Enyne [4 + 4] Photocycloaddition: Bridged 1,2,5-Cyclooctatrienes

Enyne photocycloaddition with a 2-pyridone yields a mixture of products including amide-bridged 1,2,5-cyclooctatrienes, the first examples of enyne [4 + 4] adducts. Four regio- and stereochemical isomers of the [4 + 4] adduct are possible. All appear to be too strained to be isolated, but they have been identified as their [2 + 2] cyclobutane dimers. Cyclobutane and cyclobutene adducts have also been isolated, [2 + 2] addition products possibly related to the unstable [4 + 4] adducts via Cope rearrangement. Calculations suggest that [3,3] rearrangements have high energy barriers, however, making thermal interconversion unlikely.

Tetraquinanes via [4 + 4] photocycloaddition/transannular ring closure.

Intramolecular [4 + 4] photocycloaddition of a furan and a cyclopentane-annulated 2-pyridone yields a cyclooctadiene product with four new stereogenic centers. Transannular ring closure produces the 5-5-5-5 fused ring system of the crinipellins, including three contiguous quaternary carbons, with the correct absolute stereochemistry derived from (-)-carvone.

α-Alkyl-α-aminosilanes. 1. Metalation and alkylation between silicon and nitrogen

Abstract tert-Butyl carbamate derivatives of readily available aminomethyltrialkylsilanes have been studied for their ability to undergo metalation between nitrogen and silicon, followed by reaction with an electrophile. Metalation is rapid and reaction with a variety of electrophiles proceeds efficiently. When a benzyl group is attached to nitrogen, benzylic deprotonation competes with deprotonation next to silicon. Metalation of tert-butyl carbamate derivatives of aminomethyltrimethylsilane can be used to prepare α-functionalized α-amino silanes. Download : Download full-size image