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

Abstract

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

Antitumor Potential of Conjugable Valinomycins Bearing Hydroxyl Sites: In Vitro Studies

“…In agreement with literature, 6 data in Table 1 indicate that VLM (1) displays different cytotoxic effects on the panel of selected cancer cell lines, which are dose-and time-dependent ( Figure 1); the estimated IC 50 values cover 3 orders of magnitude, ranging from the low nM for C6 and HepG2 to the low μM for MCF-7 and A2780 cell lines. However, analogues 3 and 4 evidence a similar dose-and time-dependent cytotoxic effect, although anywhere slightly less marked than 1.…”

“…7 This causes dissipation of mitochondrial transmembrane potential (ΔΨ m ) and induction of apoptosis, which has been shown in several mammalian cell types, 8,9 including a number of tumor cell lines. 6,10,11 Because of its unique properties, VLM has captured the attention of many searchers devoted to various fields of science, so that studies detailing its mechanism of action, 12−14 as well as concerning the synthesis of analogues have continued unabated over the past decades. 15 Apparently, only few studies have put forward the feasibility of VLM-based drug conjugates.…”

Synthesis, Characterization and Antibacterial Activity of New Complexes of Some Lanthanide Ions with 15-Crown-5 and 18-Crown-6

“…After (2 hrs) a clear yellow solution was obtained, filtered and treated with benzene in a separating funnel in order to extract all the excess of picric acid. The final step of crystal formation can be done by reducing the volume of the solution at (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) o C). After cooling the solution in an ice bath for (1 hr.)…”

“…The nature of these interactions is determined by the characteristics of the metal complex. For instance, all cationic metal complexes exhibit electrostatic interactions with the polyanionic DNA molecule, metal complexes with extended aromatic systems may intercalate between the DNA base pairs while mixed -ligand metal complexes were found to be particularly useful because of their high potential to bind DNA via a multitude of interactions and to cleave the duplex by virtue of their intrinsic, chemical, electrochemical and photochemical reactivities 48,49 .…”

Atypical cytostatic mechanism of N-1-sulfonylcytosine derivatives determined by in vitro screening and computational analysis

“…WI 38 (normal human fibroblasts), HeLa (cervical carcinoma), MCF-7 (breast carcinoma), SW 620 and HCT 116 (colon carcinoma), MiaPaCa-2 (pancreatic carcinoma), NCI-H460 (lung carcinoma), PC-3 (prostatic carcinoma) and OVCAR-3 (ovarian carcinoma) were cultured as monolayers and maintained in Dulbecco's modified Eagle's medium (DMEM), while HL 60 (acute promyelocytic leukemia) and MOLT-4 (acute lymphoblastic leukemia) were cultured in suspension and maintained in RPMI 1640 (Imunološki Zavod, Zagreb, Croatia) supplemented with 10% fetal bovine serum (FBS), l-glutamine (2 mM), penicillin (100 U/ml), and streptomycin (100 μg/ml) in a humidified atmosphere with 5% CO2 at 37°C. The growth inhibition activity was assessed as described previously, [39] according to the slightly modified procedure of the National Cancer Institute, Developmental Therapeutics Program.…”