Antimutagenic effect of crown ethers on heavy metal-induced sister chromatid exchanges

Abstract

Macrocyclic polyethers (crown ethers) are a family of compounds that possess the ability to complex with and transport metal ions across membranes. Because of their unique ionophoric characteristic, they have wide application in industry and research, chemistry and biology. In the current investigation the relationship between heavy metal mutagenesis and crown ether co-mutagenicity and/or antimutagenicity in mammalian cells has been examined using sister chromatid exchange (SCE) as the cytogenetic end point. Chinese hamster ovary cells were treated with lead or cadmium, with and without selected crown ethers. Several genotoxic end points, including SCEs were scored and statistically compared. We report here that most of the crown ethers studied had little or no influence on lead- or cadmium-induced SCEs or chromosome aberrations. On the other hand, the substituted crown ether dicyclohexyl 21-crown-7 significantly decreased both spontaneous and metal-induced SCE frequencies, suggesting that this crown ether may possess antimutagenic activity.

Antitumor Potential of Crown Ethers: Structure−Activity Relationships, Cell Cycle Disturbances, and Cell Death Studies of a Series of Ionophores

“…Because the studied structures possess neither a condensed aromatic moiety nor any positive charges, the absence of interaction with DNA is not surprising. These results are in accordance with Arenas et al showing that 18-crown-6 and 21-crown-7 and their dicyclohexyl derivatives are not genotoxic nor do they exhibit co-mutagenic properties …”

“…1 However, although some crown ether complexes with, for example, naphthoquinonethiol, 10 cisplatin derivatives, 11 or a bis-(propargilic) sulfone moiety, 12 showed good antitumor and/or antimicrobial activities, no systematic study has been performed on the potential antitumor ability of nonfunctionalized crown compounds. The fact that some crown ethers showed antiproliferative activity 13 and that some ionophores, such as valinomycin, an antibiotic with potassium-selective ionophoric activity, have been reported to display antitumor effects, together with the recent studies on the potential cytotoxicity caused by disrupted ion transport by Gokel group, 14,15 inspired us to check the possible antiproliferative/antitumor ability of crown ethers. We report the antiproliferative activity and structure-activity relationship of several conventional crown ethers and their derivatives in vitro and compare this activity to that of valinomycin.…”

Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents

“…This supported the concept that their toxicity is due to their interaction with membranes, and not with nucleic acids; they do not possess DNA‐damaging activity 68. 69 Moreover, it was shown that dicyclohexyl‐21‐crown‐7 has antimutagenic effects on heavy‐metal‐induced sister chromatid exchanges 70. More recently, Zasukhina et al.…”

“…Interestingly, in all experiments described above, the crown ether moieties alone were not tested in parallel with the crown‐ether‐substituted derivatives in order to assess their independent activity. In general, there are limited reports on the antiproliferative activity of crown ethers in mammalian cells,70, 89 although it has been known for more than 20 years that ionophores such as valinomycin, an antibiotic with potassium‐selective ionophoric activity, have been reported to display strong antitumor effects 90. Its use has been limited by its extreme toxicity, yet it was shown that this toxicity could be decreased by incorporating valinomycin in liposomes, while maintaining or even enhancing its antitumor activity 91.…”

Tolerability and pharmacokinetic profile of a novel benzene‐poly‐carboxylic acids complex with cis‐diammineplatinum (II) dichloride in dogs with malignant mammary tumours

“…MoA probably involves factors associated with DNA damage and repair, and with a membranotropic effect . Apoptotic pathways including preapoptotic genes are probably also involved …”