Antioxidative 1,4-Dihydropyridine Derivatives Modulate Oxidative Stress and Growth of Human Osteoblast-Like Cells In Vitro

Abstract

Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H2O2 (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H2O2 or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals.

Antioxidants and Second Messengers of Free Radicals

“…Consistent with that are the findings on the bioactivities or natural and synthetic antioxidants targeting reactive aldehydes as second messengers of free radicals in vitro or in vivo presented in the remaining papers of this Special Issue [ 14 , 15 , 16 , 17 ]. The authors of one review and two original papers were studying the structure-activity relations of particular plant extracts on their chemical composition.…”

“…The authors of one review and two original papers were studying the structure-activity relations of particular plant extracts on their chemical composition. This might help us to better understand their activity principles [ 14 , 15 , 16 ], while in the last article of this Special Issue, the authors studied the relationship between antioxidant and growth regulating effects of synthetic chemical substances, notably of 1,4-dihydropyridine derivatives (DHS) [ 17 ]. Namely, various DHPs are known for their pleiotropic activity, some also act as antioxidants that are already used for UV-protection or as antihypertensive agents.…”

“…In their original in vitro study using several well-known or newly synthesized DHPs to treat human osteoblast-like cells, the authors revealed some DHPs as possible therapeutic agents for osteoporosis. However, further research is needed to elucidate their bioactivity mechanisms in respect to signaling pathways involving HNE and related second messengers of free radicals [ 17 ].…”

Spectroscopic and electrochemical study of interactions between DNA and different salts of 1,4-dihydropyridine AV-153

“…It was shown that AV-153-Na salt possesses antimutagenic activity, enhances the DNA repair, can protect DNA against genotoxic agents, and bind DNA (Buraka et al, 2014;Leonova et al, 2018;Ryabokon et al, 2005;Ryabokon et al, 2008;Ryabokon et al, 2009). The compound also stimulates cell growth, manifests anti-apoptotic activity, and possesses antioxidant properties (Milkovic et al, 2018). Different salts of the compound were recently synthesized and subjected to investigation.…”

Synthesis, Characterization, and Anticancer Studies of Some Pyrazole‐Based Hybrid Heteroatomics

“…[6] Functionally, they can act as redoxactive synthetic compounds and hence considered as oxidative stress protectors and the inhibitors of related disorders. [7,8] Oxidative stress is extremely important in cancer studies. As the action against oxidative stress plays an important role in cellular senescence and apoptosis, DHP derivatives could be very significant in counteracting the tumor developing cellular mechanism.…”