The antimutagenicity of 2-substituted selenazolidine-4-(R)-carboxylic acids

Abstract

Selenium can have cancer chemopreventive activity, although the mechanism of action has not been well defined. Selenazolidine-4-(R)-carboxylic acids (SCAs) were devised as prodrugs of Lselenocysteine, to provide selenium in a form and at a concentration commensurate with cancer chemopreventive activity. In the present study, a series of selenazolidines has been evaluated in the Salmonella typhimurium TA98 tester strain and all were found to possess antimutagenic activity. There was little difference between the seven selenazolidines in their effectiveness against either benzo[a]pyrene (B[a]P) or 3,6-bis(dimethylamino)acridine (acridine orange), agents which differ in their requirement for mammalian enzyme bioactivation for mutagenicity. Antimutagenic activity against acridine orange was dependent on selenazolidine concentration, and EC50 values were in the 5 -10 μM range. At 25 μM, the concentration tested in common for the two mutagens, the selenazolidines were more effective antimutagens against acridine orange than against B[a]P, with reductions in mutant frequency ranging from 54-71% for B[a]P and 79-93% for acridine orange. Efficacy against B[a]P was not enhanced when the concentration was increased to 50 μM. The similarity in efficacy among the selenazolidines against B[a]P mutagenicity, contrasted with intercompound differences in their ability to inhibit S9 CYP1A activity. The CYP1A Ki values ranged from a low of 63 μM (2-[2'-hydroxyphenyl]SCA) to a high of 1.1 mM (2-cyclohexylSCA), but all were above the concentration required to inhibit mutagenicity by 50%. Thus, all the SCAs possess antimutagenic activity against both B[a]P and acridine orange, the efficacy varies little between the individual selenazolidines, and for B[a]P, the efficacy is not proportional to the inhibitory effect on the mutagen bioactivating enzyme.

TheConyza trilobaExtracts with High Chlorophyll Content and Free Radical Scavenging Activity Had Anticancer Activity in Cell Lines

“…The cytotoxicity assay was performed using the bacterial growth assay on nutrient agar plates [5]. The experiment was designed with conditions that mimic those of the revertant mutagenesis/antimutagenesis assay.…”

“…Since antimutagenic compounds are most probably to exert anticarcinogenic activity when challenged with carcinogens [4, 5], evaluation of antimutagenic activities of natural products appears to be necessary. This test as a prelude to any in vivo experimentation will save time and money in the screening pipeline.…”

New Selenoderivatives as Antitumoral Agents

“…Other interesting derivatives are 2-substituted selenazolidine-4(R)-carboxylic acids ( Figure 5). There are numerous studies that concern the induction of a protective hepatic enzyme related to gluthathione-S-tranferase and gluthathione peroxidase and it seemed of interest to evaluate these compounds in PC cells (El-Sayed et al, 2007, Poerschke & Moos 2011. …”

Convenient Carbonylative Synthesis of Selenium‐Substituted Vinyl Iodides: (E)‐5‐(Iodomethylene)‐1,3‐selenazolidin‐2‐ones

“…Selenium‐containing compounds are not only important intermediates in synthetic chemistry, and also widely applied in biological and medicinal chemistry . Among them, 1,3‐selenazolidines have been reported as inhibitors of NO‐synthase, antimutagenes and cancer‐prev enting agents . However, the developed synthetic methodologies still facing some challenges, including limited diversity of products, availability of substrates, and inconvenient reaction conditions …”