Progress towards water-soluble triazole-based selective MMP-2 inhibitors

Abstract

Water solubility is a key aspect that needs to be addressed to obtain drug-like compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole-substituted hydroxamates, we synthesized a new series of α-sulfone, α-tetrahydropyran and α-piperidine, α-sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9. This finding allowed us to pursue in vitro permeability through the Caco-2 monolayer and opened the possibility of carrying out further preclinical investigations. Docking and MD simulations have been performed in order to rationalize the biological results. The inhibitory activity of this compound against a panel of ten MMPs was determined showing an interesting MMP-2/MMP-1, -8, and -14 selectivity profile. The cytotoxicity and anti-invasive activity of the compounds on highly metastatic human fibrosarcoma tumor cells (HT1080) were determined, showing, at 10 μM concentration, a decrease in cell invasiveness up to 80%.

Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family

“…18 A large number of MMP inhibitors (MMPIs) have been reported so far. [23][24][25] The potent but not selective MMPI (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS) 26 ( Fig. The latter is considered the "selectivity pocket", as it is the region where MMPs exhibit the largest differences.…”

An Integrated Computational and Experimental Approach to Gaining Selectivity for MMP‐2 within the Gelatinase Subfamily

“…Compounds 11 a – d were obtained from alkynes 5 a – c and 8 , as shown in Scheme . From azide 9 ,13b CuAAC reactions led to the triazole family 10 a – d . Subsequent acidic removal of both Boc and THP groups afforded 11 a – d , which were isolated as dihydrochloride salts, to assure good water solubility 13b…”

“…General procedure for the preparation of triazoles 10 b – d : A mixture of 9 13b (100 mg, 0.20 mmol, 1.00 equiv), the appropriate alkyne (0.26 mmol, 1.30 equiv), freshly made aqueous CuSO 4 ⋅ 5 H 2 O solution (0.1 M , 118 μL, 0.01 mmol, 0.06 equiv) and sodium ascorbate solution (0.5 M , 78 μL, 0.04 mmol, 0.20 equiv) in DMF (1–3 mL) was stirred at RT under argon for 16–24 h. The reaction mixture was partitioned between CH 2 Cl 2 and water. The organic layer was washed with aqueous ammonia (15 %), water and brine, dried over anhydrous MgSO 4 , filtered and concentrated.…”

“…Azide cores bearing the hydroxamate zinc binding group (ZBG) were clicked to fragments designed to interact with the S1′ pocket. This work led to the discovery of 1 (Scheme ), a potent, water‐soluble MMP‐2 inhibitor that displayed a promising MMP‐2/MMP‐9 selectivity 13b. The present work reports our efforts to explain and improve the selectivity of compound 1 .…”

Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs)

“…This review summarizes the main achievements in the field of MMPIs imaging probes and constitutes an important contribution to support further research in this area. Our research group has designed, in the last years, highly potent and selective inhibitors of MMP-2, while avoiding other MMPs, including the highly homologous gelatinase MMP-9 [114,115,116,117,118]. The structure based drug design on MMP-13 carried out by the authors has also provided very interesting and highly selective inhibitors [119].…”