Discovery of 7-aminophenanthridin-6-one as a new scaffold for matrix metalloproteinase inhibitors with multitarget neuroprotective activity

Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(5H)-one Derivatives against Metal-Induced Cell Death and Oxidative Stress in SN56 Cells

“…In our previous work, we showed that APHs are able to inhibit MMP enzymes and computational studies suggested that this inhibitory activity is not mediated by the chelation of Zn 2+ ion at the catalytic site, as is the case for many other MMP inhibitors. 17 Our present results show that APH compounds tested were not able to chelate Zn 2+ ion, confirming the computational results. Further analysis should be performed to determine the mode of action behind MMPs inhibition by APHs .…”

“…The target compounds APH1 – APH5 were synthesized as shown in Scheme 1 by our previously reported method. 17 Thus, 4,6-diaryl-5,6-dihydroanthranylate derivatives 1 were obtained by a CAN-catalyzed multicomponent reaction between ortho -nitrochalcone, ethyl acetoacetate, and the suitable primary amines. This was followed by oxidative dehydrogenation of the central ring in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and reductive cyclization to give the target compounds APH1 – APH5 in good overall yield.…”

“…For the current study, we selected compounds APH1 – APH5 from our library, due to their higher activity on the selected targets (i.e., MMPs inhibition and antioxidant activity), according to our previous studies. 17 …”

“…In this sense, we have previously reported the discovery of new multitarget phenanthridin-6( 5H )-one derivatives (APH) that are able to inhibit MMP enzymes, reduce oxidative stress, and protect against ROS. 17 Although these compounds were designed to present chelating activity, computational studies indicated binding to a distal region at the S1′ site, with no involvement of the catalytic zinc ion. 16 Thus, it is necessary to confirm experimentally the role of the Zn 2+ ion in MMPs inhibition by these compounds.…”

“…The induction of cellular antioxidant enzymes, which reduce ROS, may also be involved, since they show neuroprotective and antioxidant action against hydrogen peroxide in SN56 cells. 17 Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in the transcription regulation of antioxidant cytoprotective enzymes such as superoxide dismutase 1, catalase, glutathione peroxidase, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1, among others. 18 − 20 Dysfunction of the Nrf2 pathway has been identified, in different neurodegenerative diseases, as a factor of oxidative stress generation.…”