alpha-Biphenylsulfonylamino 2-methylpropyl phosphonates: enantioselective synthesis and selective inhibition of MMPs

Bioorg Med Chem. 2007 Jan 15;15(2):791-9. doi: 10.1016/j.bmc.2006.10.047. Epub 2006 Oct 25.


(R)-alpha-Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, alpha-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-p-bromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-alpha-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1, -2, -3, -7, -8, -9, -13 and -14 showed IC(50) in the range of nM in most cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / pharmacology*
  • Humans
  • Indicators and Reagents
  • Isoenzymes / antagonists & inhibitors
  • Magnetic Resonance Spectroscopy
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Recombinant Proteins
  • Spectrophotometry, Ultraviolet
  • Stereoisomerism
  • Structure-Activity Relationship


  • Biphenyl Compounds
  • Indicators and Reagents
  • Isoenzymes
  • Matrix Metalloproteinase Inhibitors
  • Organophosphonates
  • Protease Inhibitors
  • Recombinant Proteins