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Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with Λ-helicity at the metals becomes more potent than the Δ compound with increasing exposure time. From concentration- and temperature-dependent 57Fe isotopic labelling studies of cellular accumulation we postulate that while the more potent Λ enantiomer undergoes carrier-mediated efflux, for Δ the process is principally equilibrative. Cell fractionation studies demonstrate that both enantiomers localise in a similar fashion; compound is observed mostly within the cytoskeleton and/or genomic DNA, with significant amounts also found in the nucleus and membrane, but with negligible concentration in the cytosol. Cell cycle analyses using flow cytometry reveal that the Δ enantiomer induces mild arrest in the G1 phase, while Λ causes a very large dose-dependent increase in the G2/M population at a concentration significantly below the relevant IC50. Correspondingly, G2-M checkpoint failure as a result of Λ-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Δ compound, a quite specific mode of binding, probably in the major groove. Further, spindle assembly checkpoint (SAC) failure, which could also be responsible for the observed G2/M arrest, is established as a feasible mechanism for the Λ helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the Λ compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Δ promotes depolymerization and more subtle changes in microtubule and actin networks. [ABSTRACT FROM AUTHOR]

The oxidation of cis‐[Pt(NH3)2(OAc)2] with H2O2 yields a mixture of two isomers: ctc‐[Pt(NH3)2(OH)2(OAc)2] and ctc‐[Pt(NH3)2(OH)(OAc)(OH)(OAc)]. Following modification with 4‐phenylbutyric (PhB) anhydride, two isomers were separated and characterized; the symmetric ctc‐[Pt(NH3)2(PhB)2(OAc)2] (1) and the nonsymmetric ctc‐[Pt(NH3)2(PhB)(OAc)(PhB)(OAc)] (2). They differ in their log P values and despite having similar cellular uptake and similar DNA platination levels, the symmetric ctc‐[Pt(NH3)2(OH)2(OAc)2] is more than 4‐fold more potent than the nonsymmetric isomer in a panel of 4 cancer cell lines. [ABSTRACT FROM AUTHOR]