Diastereoselective Solution and Multipin-Based Combinatorial Array Synthesis of a Novel Class of Potent Phosphinic Metalloprotease Inhibitors

• Published in: Chemistry : a European journal 2003-05, Vol.9 (9), p.2079-2094
• Main Authors: Makaritis, Anastasios, Georgiadis, Dimitris, Dive, Vincent, Yiotakis, Athanasios
• Format: Article
• Language: English
• Subjects: combinatorial chemistry; Combinatorial Chemistry Techniques; Cyclization; cycloaddition; Indicators and Reagents; inhibitors; Kinetics; Magnetic Resonance Spectroscopy; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - antagonists & inhibitors; metalloproteins; Phosphinic Acids - chemical synthesis; Phosphinic Acids - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology; solid-phase synthesis; Solutions; Stereoisomerism
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200204456

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 Punprotected 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 (Ki in the range of few nM). Optically pure phosphinic pseudopeptides, bearing a propargylic side chain at P1′ position, were prepared. 1,3‐Dipolar addition of nitrile oxides onto these dipolarophiles, in solution and solid phase (multipin technology), was successfully exploited to afford a novel class of isoxazole‐containing phosphinic peptides such as depicted. These peptides behave as very potent inhibitors of MMPs.