Silanediols

Silicon, right below carbon on the periodic table, shares many of the same attributes, such as bonds to four tetrahedrally arrayed substituents and strong bonds to carbon.  Silicon is far more abundant than carbon, but mostly in the form of silica, with bonds only to oxygen, earth's most abundant element.  Organic derivatives of silicon do not occur naturally.[1]  Dialkyl and diarylsilanediols are best known as unstable precursors of silicones, which form by dehydrative polymerization.  Silicones are well known for their outstanding thermal stability, fluid properties and low toxicity.[2]  The notion that silanediols are unstable is reinforced by the huge annual production  of dimethylsilanediol.  This smallest of the dialkylsilanediols is intrinsically unstable and spontaneously yields permethylsilicone.  As the organic substituents increase in bulk, polymerization is inhibited, and highly stable examples are also well known.  More than 100 silanediols have been characterized.[3] 


 
Unlike hydrated carbonyls (carbondiols) that readily dehydrate and form carbon–oxygen double bonds, silanes form silicon–oxygen double bonds only under forcing conditions.  The intrinsic tetrahedral stability of silanediols, along with their close relationship to carbon and low toxicity, makes them good candidates for mimics (bioisosteres) of hydrated carbonyls.  Hydrated carbonyl analogs are central to designed inhibitors of proteolytic enzymes (proteases).[4]  Substitution of a silanediol into the backbone of a polypeptide would result in a molecule that can be recognized by a protease, bind to its active site, and inhibit it.  Silanediols are outstanding hydrogen bond donators (better than alcohols) and at the same time equivalent in their abilities to accept hydrogen bonds.  This excellent hydrogen bonding can be seen in the X-ray structures of silanediols, and also in properties such as the liquid crystallinity of diisobutylsilanediol.  One such crystal structure for diphenylsilanediol is shown.  Good hydrogen bonding will promote binding at the active site of the aspartic proteases, one of the four classes of proteases.  The HIV protease is the best known aspartic protease.



 
Metalloproteases are another important class of protease, with a zinc ion at the active site that is critical to hydrating and cleaving the peptide bond.  Captopril was the first drug designed as a protease inhibitor, targeting the metalloprotease angiotensin-converting enzyme (ACE).  Could silanediols act as metalloprotease inhibitors?  The precedent for metal chelation by silanediols is sparse.  To test silanediols as metalloprotease inhibitors, we prepared a silanediol analog of a known ketone inhibitor.[5]  Ketones can act as analogs of amides and are generally thought to bind to a protease active site as the hydrate.  Two types of silanols were prepared, a silanediol and a methylsilanol.  Both were prepared as a mixture of diastereomers.  The silanediol was a very good inhibitor, with an IC50 of 14 nM (the concentration needed to inhibit 50% of the enzyme, the lower this value the better).[6]  It is likely that most of the inhibition is derived from only one of the four diastereomers.  The methylsilane was a very poor inhibitor, suggesting that the silanediol acts by chelating the active site zinc.  Note that in this exercise we prepared the silanediol with an isobutyl group between silicon and nitrogen.  The results from testing a silanediol with the ‘correct’ benzyl group and control of stereochemistry are expected very soon. 

To test the silanediol as an inhibitor of the HIV protease, an aspartic protease, a C2 symmetric silanediol was prepared, modeled on a known, nearly C2 symmetric, carbinol.  The silanediol proved to be quite potent, with a Ki value of 2.7 nM.  The carbinol and indinavir (one of the currently marketed HIV treatments) are more potent against the enzyme, but only by a factor of about 7.  This relative potency holds true in whole cell protection assays as well, where the drug candidate must cross cell membranes in order to demonstrate its inhibitory properties. [7]

We are continuing the work described above, and expanding it to other enzymes and other enzyme classes.

References

  1. General organosilane reviews: Rochow, E. G. Silicon and Silicones; Springer-Verlag: New York, 1987.  Rösch, L.; John, P.; Reitmeier, R. "Organic Silicon Compounds," In Ullmann's Encyclopedia of Industrial Chemistry; 5th ed.; B. Elvers; S. Hawkins; W. Russey and G. Schulz, Ed.; VCH: New York, 1993; Vol. A24; pp 21-56.
  2. Reviews of bioactive organosilanes: Tacke, R.; Linoh, H. "Bioorganosilicon Chemistry," In The Chemistry of Organic Silicon Compounds; S. Patai and Z. Rappoport, Ed.; John Wiley & Sons: New York, 1989; Vol. 2; pp 1143-1206. Sieburth, S. McN. "Isosteric Replacement of Carbon with Silicon in the Design of Safer Chemicals," In Designing Safer Chemicals; S. C. DeVito and R. L. Garrett, Ed.; American Chemical Society: Washington, DC, 1996. Tacke, R.; Wagner, S. A. "Chirality in Bioorganosilicon Chemistry," In The Chemistry of Organic Silicon Compounds; Z. Rappoport and Y. Apeloig, Ed.; John Wiley & Sons: New York, 1998; Vol. 2; pp 2363-2400.
  3. Review:  Lickiss, P. D. "The Synthesis and Structure of Organosilanols," Adv. Inorg. Chem. 1995, 42, 147-262.
  4. Leung, D.; Abbenante, G.; Fairlie, D. P. "Protease Inhibitors: Current Status and Future Prospects," J. Med. Chem. 2000, 43, 305-341.
  5. Almquist, R. G.; Crase, J.; Jennings-White, C.; Meyer, R. F.; Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Kaplan, H. R. "Derivatives of the Potent Angiotensin Converting Enzyme Inhibitor 5-(S)-Benzamido-4-oxo-6-phenylhexanoyl-L-proline: Effect of Changes at Position 2 and 5 of the Hexanoic Acid Portion," J. Med. Chem. 1982, 25, 1292-1299.
  6. Sieburth, S. McN.; Nittoli, T.; Mutahi, A. M.; Guo, L. "Silanediols: A New Class of Potent Protease Inhibitors," Angew. Chem. Int. Ed., Engl. 1998, 37, 812-814.
  7. Chen, C.-A.; Sieburth, S. McN.; Glekas, A.; Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffrey, S.; Klabe, R. M. "Drug Design with a New Transition State Analog of the Hydrated Carbonyl: Silicon-Based Inhibitors of the HIV Protease," Chem. Biol. 2001, in press.

Last modified: October 2001