Oxidative Degradation of High-Molar-Mass Hyaluronan: Effects of Some Indole Derivatives to Hyaluronan Decay

Abstract

Indole derivatives such as isatin (a natural compound), cemtirestat, stobadine, and its derivatives (synthetic compounds) are known to have numerous positive effects on human health due to regulation of oxidative status. The aim of the study was to assess radical scavenging capacities of these compounds and explore their potential protective effects against reactive oxygen species formed during Cu(II) ions and ascorbate-induced degradation of high-molar-mass hyaluronan. Based on the IC50 values determined by the ABTS assay, the most effective compound was SM1M3EC2·HCl reaching the value ≈ 11 µmol/L. The lowest IC50 value reached in the DPPH assay was reported for cemtirestat ≈ 3 µmol/L. Great potency of inhibition of hyaluronan degradation was shown by cemtirestat, followed by isatin even at low concentration 10 µmol/L. On the other hand, stobadine·2HCl had also a protective effect on hyaluronan degradation, however at greater concentrations compared to cemtirestat or isatin. SME1i-ProC2·HCl reported to be a less effective compound and SM1M3EC2·HCl can be considered almost ineffective compared to stobadine·2HCl. In conclusion, our results showed that both isatin and cemtirestat were capable of attenuating the degradation of high-molar-mass hyaluronan due to their ability to complex/sequester cupric ions.

Design, Synthesis, Biological Evaluation and Molecular Docking of Pyrrole-Based Compounds as Antioxidant and Mao-B Inhibitory Agents

“…Therefore, the piperazine moiety could be examined as a potent scaffold for a future design of novel antioxidants. The latter results are in good agreement with recent papers which have discussed good radical scavenging activities of numerous substituted piperazines [17,29,31]. Interestingly, the valine-based pyrrole derivatives did not demonstrate any antioxidant properties after both assays.…”

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

“…Apparently, there are several advantages of cemtirestat over the clinically used epalrestat, namely lower molecular weight, better water solubility, higher AR inhibition activity recorded both at the level of isolated enzyme ( Table 2 and Table 4 ) and at the organ level of isolated rat eye lenses ( Table 13 ) and additional AO action ( Table 10 and Table 11 , Figure 15 and Figure 16 ). Recently, antioxidant activity of cemtirestat was corroborated by a study of Valachova et al [ 96 ] reporting ability of the drug to protect hyaluronan against oxidatively induced degradation. In addition, protective effects of cemtirestat in neuron-like PC12 cells and BV2 rodent microglial cells exposed to toxic models of oxidative stress were recently documented [ 97 , 98 ].…”

“…Among the novel derivatives, compound 5a was patented (P3). At the present time, it is in the stage of complex preclinical evaluation under the name of cemtirestat [ 76 , 78 , 87 , 88 , 89 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. Apparently, there are several advantages of cemtirestat over the clinically used epalrestat, namely lower molecular weight, better water solubility, higher AR inhibition activity recorded both at the level of isolated enzyme ( Table 2 and Table 4 ) and at the organ level of isolated rat eye lenses ( Table 13 ) and additional AO action ( Table 10 and Table 11 , Figure 15 and Figure 16 ).…”

Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

“…[104] Moreover, administration of cemtirestat for two months in an animal diabetes model improved symptoms of peripheral neuropathy by reducing sorbitol levels and oxidative stress (determined as TBARS) in plasma. [105] Recent studies on the toxicological profile of cemtirestat were conducted [106] and its effect on other parameters, such as triglyceride levels [107] and hyaluronic acid, [108] its activity in various cell lines was evaluated as well. [109,110] These results agree on cemtirestat's further clinical evaluation for its development towards a useful agent for treating diabetic complications.…”