The Wonders of Sulfones:
Surrogates of Pyrophosphate for the Development of Substrate Analogs and as Inhibitors of Glycosyltransferases and HIV Replication

Urvashi Sahni, Jessica Wong and Ivy Kekessie

Sulfone analogs are known to inhibit the activity of glycosyl transferases in cancer and the replication of HIV–1. These analogs were synthesized primarily to mimic phosphate backbones. Biological evaluation of these analogs revealed the following advantages:

• The non-charged nature of sulfones helps increase cellular penetration.

• Enzyme-ligand interaction is favored when sulfones complex with metals like manganese and magnesium present in glycosyl transferase and HIV-1 IN respectively.

• The C-glycoside linked sulfone analogs are more stable than O-glycosides thus preventing enzymatic degradation of these analogs.



Synthesis of Monosulfone and Disulfone Reagent: The Core Reagent for Making Our Target Analogs
  
Disulfone Reagent Crystals Crystal Structure of Monosulfone Reagent.

A variety of aldehydes can be coupled to both disulfone and monosulfone reagents via Horner-Emmons-Wadsworth olefination reactions to produce symmetrical or unsymmetrical vinyl sulfone coupled compounds as shown below.



Crystal structure of Disulfone Reagent



Therapeutics Targeting Cancer
Complex oligosaccharides are synthesized by glycosyltransferases in the ER and Golgi complex by the sequential transfer of sugar residues from nucleotide to growing polysaccharide chains. Since carbohydrates are important recognition molecules in biological systems, the profound impact of glycosyltransferases on life processes has made them desirable targets for inhibition. The transferases that have been studied for inhibition include galactosyltransferases, fucosyltransferases, sialyltransferases, N-acetylglucosaminyltransferases, glucose ceramide synthase, and oligosaccharyl transferase. However, most of the inhibitors developed to date are charged, which poses problems in cellular transport mechanisms. In this context,we devised new analogs of glycosyltransferases in which the crucial diphosphate linkage is replaced by a non-charged isostere. As potential product-like inhibitors of glycosyltransferase.

Crystal Structure of bacterial
Sialyltransferase with CMP-3FNeuAc (structure in middle) in each monomer.
http://www.nature.com/nsmb/journal/vll/n2/pdf/nsmb 720.pdf
 CMP-3FNeuraminic Acid
Monomer of Sialyltransferase
http://www.nature.com/nsmb/journal/vll/n2/pdf/nsmb 720.pdf



Direct Inactivation of HIV and Inhibition of HIV Integrase�
DCM 205, a vinyl sulfone analog of L-chicoric acid (LCA a known HIV-1 integrase inhibitor), was synthesized for the initial purpose of targeting HIV-1 integrase. Integrase, along with reverse transcriptase and protease, are the three essential enzymes required by HIV-1 for replication. Time-of-addition and biacore studies revealed that DCM205 also inhibits at an earlier stage during the viral replication cycle and directly deactivates HIV-1. These important properties exhibited by DCM205 makes it a significant candidate for development as a form of topical HIV-1 treatment (HIV-1 microbicides). Several analogs of DCM205 are thus being synthesized and analyzed for their direct inactivation and integrase enzyme inhibitory properties.

HIV-1 Viral Particle
http://www.aids-info.ch/e_te/aas-e-imm.htm


Crystal Structure of Integrase

Acknowledgments: National Science Foundation CHE-0196482, NSF CRIF  program (CHE-9808183), NSF Grant OSTI 97-24412 and NIH Grant RR11973 provided funding for the NMR spectrometers used on this project. Also, this project was supported by TRDRP 12RT-0254. California Research Center for the Biology of HIV in Minorities (for I.K.)


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