Diastereoselective solution and multipin-based combinatorial array synthesis of a novel class of potent phosphinic metalloprotease inhibitors.
The solution-phase synthesis and resolution of new phosphinopeptidic building blocks containing a triple bond was realized in high yields and optical purities (units 3 a-d). The absolute configuration of the target compounds was unambiguously established by NMR studies. A post-assembly diversification strategy of these blocks was developed through 1,3-dipolar cycloaddition of a variety of in situ prepared nitrile oxides. This strategy led to the rapid and efficient diastereoselective preparation of a novel class of isoxazole-containing phosphinic peptides (peptides 5 a-i). Solid-phase version of this strategy was efficiently achieved on multipin solid technology, by developing a new protocol for the coupling of P-unprotected dipeptidic blocks with solid supported amino acids in a quantitative and diastereoselective manner. Optimization of dipolar cycloadditions onto pin-embodied phosphinic peptides allowed the convenient preparation of this new class of pseudopeptides. The crude phosphinic peptides (9 a-k) were obtained in high yields and purity as determined by RP-HPLC. Inhibition assays of some of these peptides revealed that they behave as very potent inhibitors of MMPs, outmatching previously reported phosphinic peptides, in terms of potency (K(i) in the range of few nM).
University of Athens, Department of Chemistry, Laboratory of Organic Chemistry, Panepistimiopolis, Zografou 157 71, Athens, Greece.
Anastasios
A
Makaritis
Dimitris
D
Georgiadis
Vincent
V
Dive
Athanasios
A
Yiotakis
D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D012996:Solutions; D013237:Stereoisomerism
D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D012996:Solutions; D053509:Matrix Metalloproteinase 13; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases