alpha-Biphenylsulfonylamino 2-methylpropyl phosphonates: enantioselective synthesis and selective inhibition of MMPs.
(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.
Biasone
Alessandro
A
Dipartimento di Scienze del Farmaco, Università "G. d'Annunzio", Via dei Vestini 31, 66013 Chieti, Italy.
Tortorella
Paolo
P
Campestre
Cristina
C
Agamennone
Mariangela
M
Preziuso
Serena
S
Chiappini
Marika
M
Nuti
Elisa
E
Carelli
Paolo
P
Rossello
Armando
A
Mazza
Fernando
F
Gallina
Carlo
C
D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D007202:Indicators and Reagents; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D011480:Protease Inhibitors; D011994:Recombinant Proteins