Dihydropyridine Derivatives as Cell Growth Modulators In Vitro

Abstract

The effects of eleven 1,4-dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (3H-thymidine incorporation) were compared with their antiradical activities (DPPH assay), using well-known DHP antioxidant diludine as a reference. Thus, tested DHPs belong to three groups: (1) antioxidant diludine; (2) derivatives with pyridinium moieties at position 4 of the 1,4-DHP ring; (3) DHPs containing cationic methylene onium (pyridinium, trialkylammonium) moieties at positions 2 and 6 of the 1,4-DHP ring. Diludine and DHPs of group 3 exerted antiradical activities, unlike compounds of group 2. However, novel DHPs had cell type and concentration dependent effects on 3H-thymidine incorporation, while diludine did not. Hence, IB-32 (group 2) suppressed the growth of HOS and HeLa, enhancing growth of L929 cells, while K-2-11 (group 3) enhanced growth of every cell line tested, even in the presence of doxorubicin. Therefore, growth regulating and antiradical activity principles of novel DHPs should be further studied to find if DHPs of group 2 could selectively suppress cancer growth and if those of group 3 promote wound healing.

Pleiotropic Properties of Amphiphilic Dihydropyridines, Dihydropyridones, and Aminovinylcarbonyl Compounds

“…For example, LD 50 values for compounds 10 , 12 , and 13 were 1482, 1431, and 1706 mg/kg, respectively, while cytotoxicity towards HT-1080 cells was 3–10 μ g/ml and towards MH-22A cells was 3–40 μ g/ml. In principle, the obtained data coincide with observations on the impact of dihydropyridine on cell growth, where it was concluded that a long alkyl chain containing 1,4-DHP amphiphiles show promising dual activity—proliferation inhibition on cancer cell lines and proliferation stimulating effect on normal cell lines [ 31 ]. It should be noted that the 3,5-bis(dodecyloxycarbonyl)-1,4-DHP amphiphile 14 with an electron-withdrawing acetyl group in the pyridinium moieties in positions 2 and 6 of the 1,4-DHP ring was practically nontoxic on noncancerous NIH3T3 cells and demonstrated selective cytotoxicity toward cancer cells and pronounced cytotoxicity of around 3 μ g/ml on HT-1080 cells and of 50-100 μ g/ml on MH-22A cells.…”

“…1 – 24 , Table 1 ) could be considered as analogues of 1,4-dihydronicotinamide and model compounds of redox coenzyme NAD(P)H. Many 4-aryl-1,4-DHPs possess antioxidant properties, including several Ca 2+ channel blockers [ 53 ]. The antiradical activity (ARA) of two 1,4-DHPs containing cationic moieties was determined by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay; the results were expressed as a percentage (%) of the DPPH free radical scavenging, and the untreated level of the DPPH radical was designated as 100% [ 13 , 31 ]. It was demonstrated that 3,5-didodecyloxycarbonyl-4-phenyl-1,4-dihydropyridine derivatives containing pyridinium moieties showed 25–60% radical scavenging activity which are comparable with the ARA of Diludin [ 54 ] (40%)—a widely known antioxidant.…”

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

“…Since previous studies have shown that various DHPs can achieve modulation of cellular responses to oxidative stress and thus influence cell growth and differentiation [ 30 , 48 ], the major aim of the current study was to find a DHP compound or a group of them that will act as potential antioxidants and could modify the growth of human–osteoblast cells indicating their possibly beneficial effects for treatment of osteoporosis and related bone disorders. Since oxidative stress was implicated in pathogenesis of osteoporosis (manifested as deterioration of bone) and antioxidants, such as lycopene and polyphenols have been suggested to benefit the therapy of osteoporosis [ 17 , 19 , 49 ], we studied the antioxidative potential of the selected DHPs which were 10-fold more effective than uric acid on HOS cells in mild oxidative stress conditions.…”

“…The studied 27 DHP compounds belong to several (five, I – V , see Table 1 ) relative types. All tested DHPs were synthesized at the Latvian Institute of Organic Synthesis [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Already described compounds are referenced in Table 1 ; new compounds have been synthesized by making use of methods indicated below for each type and indexed as MM (*MM) in Table 1 .…”

4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action

“…Antiviral activity of analogues of the presented six compounds has been described [25]. Besides, close analogues of the mentioned compounds were found to possess cell growth modulator properties [26].…”