Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry

Abstract

A series of 4-[(triazolyl)methoxy]phenyl analogs of the phenoxyphenyl-substituted thiirane SB-3CT 1 was evaluated for its ability to inhibit gelatinases, members of the matrix metalloproteinase family of enzymes. The triazole segment of these inhibitors was assembled using the Meldal-Sharpless copper-catalyzed Huisgen dipolar cycloaddition of an azide and a terminal alkyne. While these triazole derivatives possessed fair activity as gelatinase inhibitors, an intermediate used in the dipolar cycloaddition, 4-(propargyloxy)phenyl derivative 2, showed very good activity (>50% inhibitory activity following a 3 h pre-incubation of 2 at a concentration of 3 µM) as an inhibitor of human matrix metalloproteinase-2.

New clicked thiirane derivatives as gelatinase inhibitors: the relevance of the P1′ segment

“…Insufficient interactions at the S1' pocket -for instance in azide 6 that misses a P1' fragment -or too rigid/bulky P1' groups may destabilize the inhibitor binding and thus affect the turn over of the thiirane opening, as suggested by our comparative MD simulation studies. This hypothesis could explain the weak potency of inhibitors 8 (previously reported 25 ) and inhibitors 2a and 2b that bear bulky P1' fragments.…”

“…In a similar attempt to apply click chemistry to the synthesis of thiirane-based gelatinase inhibitors by Mobashery's group, 25 they obtained compounds 8 (Figure 3) that showed to be weak inhibitors of MMP-2 (in general, more than 50% of remaining MMP-2 activity at 30 µM final concentration and after 3 h of incubation). The authors suggested that the presence of a two atoms link (-CH 2 O-) between the triazole and phenyl rings could be the cause of the lack of activity.…”

“…However only weak gelatinases inhibitors were obtained. 25 The catalytic zinc ion of the MMP is represented in magenta and the S1' pocket is symbolized by orange dots. Numbering of the full proMMP-2 is used in this work.…”

“…13,32 Here we report the discovery of a hit compound (2f) that showed submicromolar activity against MMP-2, thus improving the potency of the clicked thiirane derivatives previously reported by Mobashery group in their attempt to improve the metabolic behaviour of SB-3CT. 25 To design our compounds, we connected the azide core containing the latent-ZBG to the series of alkynes that provided the most potent inhibitors in our previous work, 27 as well as to two new alkyne fragments (Figure 2). Docking studies and molecular dynamics (MD) experiments have been performed in order to rationalize the difference of inhibitory activity between 2f and the reference compound SB-3CT.…”

“…However only weak gelatinases inhibitors were obtained. 25 We previously reported a series of highly potent triazole based MMP-2 inhibitors with hydroxamate as ZBG obtained following the click-chemistry approach, 27,28 in which an azide containing segment was connected to a series of alkynes (named P1 0 fragments according to Schechter and Berger nomenclature 29 ) designed to interact with the lipophilic residues of the S1 0 pocket. This work led to inhibitors with high selectivity for MMP-2 over MMP-9.…”