Design, synthesis, and biological evaluation of new heterocycles bearing both silicon and phosphorus as potent MMP‐2 inhibitors

Abstract

Matrix metalloproteinases (MMPs) attracted medicinal chemists as they are biological targets that are involved in various pathophysiological processes such as extracellular matrix protein degradation, cell-surface receptor release and cleavage, tumor growth, homeostatic control, and innate immunity. New heterocycles, bearing both silicon and phosphorus in their molecular structures, were successfully produced via reacting silylated isocyanates and/or isothiocyanates with appropriate phosphorus ylides. Reacting nucleophilic phosphacumulenes (2,6) with isocyanate 1 and isothiocyanate 9 yielded fourmembered ring heterocycles containing phosphorus and silicon (4 and 11) and six-membered rings heterocycles (5, 8 and 12). Moreover, novel heterocycles containing two phosphorus atoms and one silicon atom were produced by the reaction of diphosphorane 13 with 1 or 9. On the other side, four-membered (23, 26 and 29a) and six-membered heterocyclic derivatives (20b and 29b) containing two phosphorus atoms in their structures were also obtained from the reaction of phosphallene ylide 13 and substrates (18, 21, 24 and 27). All the final compounds were tested for their MMP-2 inhibitor activity showing IC 50 values in the range of 0.0408-0.4985 μM. The thiolactam derivative 11 and the azaphosphetidin-4-one derivative 15, both bearing silicon and phosphorous, showed the highest activity with IC 50 values of 0.0408 and 0.0693 μM, respectively, both are significantly higher than that of quercetin (IC 50 = 0.1631 μM). Docking simulations were carried out for the most two active compounds 11 and 15 in the vicinity of the active site of MMP-2 enzyme and both formed coordinate bonds with the zinc cation key interaction for MMP-2 enzyme. In conclusion, compounds 11 and 15 can be considered as potential MMP-2 inhibitors and can be subjected to further studies as antimetastatic agents.

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

“…In recent years, computational chemistry techniques along with machine-learning and artificial intelligence approaches [ 87 ] have been extensively explored for designing effective MMP-2 inhibitors [ 65 , 66 , 67 , 88 , 89 , 90 , 91 ] with particular binding patterns. This has enabled the development of numerous small-molecule MMP-2 inhibitors that have shown promising preclinical results [ 25 , 68 , 88 , 92 , 93 , 94 , 95 ].…”

“…Different synthesis techniques have executed a major impact on the development of MMP-2 inhibitors through the modification and optimization of lead compounds [ 65 , 66 , 67 , 88 , 96 ]. The synergy between computational chemistry and synthesis techniques has allowed researchers in the last decade to develop new small-molecule MMP-2 inhibitors, as shown in Table 3 , specifically designed to target MMP-2 [ 25 , 29 , 65 , 66 , 88 , 96 ]. These inhibitors have been demonstrated to exhibit antitumor effects in both in vitro and in vivo [ 65 , 66 , 88 , 96 ].…”

“…The synergy between computational chemistry and synthesis techniques has allowed researchers in the last decade to develop new small-molecule MMP-2 inhibitors, as shown in Table 3 , specifically designed to target MMP-2 [ 25 , 29 , 65 , 66 , 88 , 96 ]. These inhibitors have been demonstrated to exhibit antitumor effects in both in vitro and in vivo [ 65 , 66 , 88 , 96 ].…”

New 3-Aminopropylsilatrane Derivatives: Synthesis, Structure, Properties, and Biological Activity

“…For instance, sila-isosteres exhibit better stability, lipophilicity, bioavailability, efficiency, and safety compared with their analogs. Generally, the strategy of bio-sila-isosterism has promising outcomes, and Si-containing structures can become highly effective agents against severe diseases, such as hypertension, diabetes mellitus, HIV, and cancer [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”