Silanediols: A New Class of Potent Protease Inhibitors

Abstract

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.

Synthesis and structural study of precursors of novel methylsilanediols by IR and Raman spectroscopies, single-crystal X-ray diffraction and DFT calculations

“…As concerns compound 3, the eclipsed orientation was discarded following X-ray structural analysis, albeit it was found to be the global minimum in gas phase. Only intermediate (3) was suitable for study by single-crystal X-ray diffraction. The so-called conformers gauche+ and gaucheÀ are both present in the crystal structure of the sample, whose packing is dominated by pAp stacking interactions (edge-to-face and offset).…”

“…In this respect, a review of the literature reveals that phenyls groups could be removed afterwards using an excess of triflic acid ATfOHA in methylene chloride at 0°C, followed by addition of ammonium hydroxide [3,[24][25][26].…”

“…This close chemical analogy has been the inspiration for many studies of silicon as a potential replacement for carbon, particularly in biologically active molecules [1,2]. The most notable example of this is the claim of silanediols as bioisosteres of the hydrated amido group and their application in the development of peptidomimetics as protease inhibitors [3,4]. The gem-silanediol group is most stable in its tetrahedral configuration than the corresponding geminal carbinol that readily undergo dehydration and, therefore, interaction with active site of protease is favored through hydroxyl groups which are excellent hydrogen bond donors and acceptors [5][6][7].…”

Catalytic enantioselective addition of Grignard reagents to aromatic silyl ketimines

“…Organic compounds with one or more carbon atoms replaced by silicon are increasingly popular in medicinal chemistry, because of several attractive characteristics of silicon atoms, such as their similar valency and tetrahedral bonding pattern, lipophilic nature and their low toxicity18. For instance, α-silyl amine motifs with trisubstituted carbon stereocentres were recently used in the synthesis of peptide isosteres and are also present in several effective proteolitic enzyme inhibitors1920. In contrast, chiral α-silyl amines with tetrasubstituted carbon have not been investigated yet, due to a lack of synthetic methods to access them.…”

Exploring Organosilane Amines as Potent Inhibitors and Structural Probes of Influenza A Virus M2 Proton Channel

“…In the first class, a quaternary carbon is replaced with a silicon to increase hydrophobicity 19 (Scheme 1 a). In the second class, a carbonyl is replaced with a sterically hindered silanediol to mimic the high-energy intermediate of an amide bound hydrolysis, provides opportunities to inhibit proteins such as proteases 20 (Scheme 1 b). …”