Preparation, cytotoxic activity and DNA interaction studies of new platinum(II) complexes with 1,10-phenanthroline and 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives.

This work describes the synthesis, characterization and in vitro anticancer activity of two platinum(II) complexes of the type [Pt(L1)2(1,10-phen)] 1 and [Pt(L2)2(1,10-phen)] 2, where L1 = 5-heptyl-1,3,4-oxadiazole-2-(3H)-thione, L2 = 5-nonyl-1,3,4-oxadiazole-2-(3H)-thione and 1,10-phen = 1,10-phenanthroline. As to the structure of these complexes, the X-ray structural analysis of 1 indicates that the geometry around the platinum(II) ion is distorted square-planar, where two 5-alkyl-1,3,4-oxadiazol-2-thione derivatives coordinate a platinum(II) ion through the sulfur atom. A chelating bidentate phenanthroline molecule completes the coordination sphere. We tested these complexes in two breast cancer cell lines, namely, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both cells, the most lipophilic platinum compound, complex 2, was more active than cisplatin, one of the most widely used anticancer drugs nowadays. DNA binding studies indicated that such complexes are able to bind to ct-DNA with Kb values of 104 M-1. According to data from dichroism circular and fluorescence spectroscopy, these complexes appear to bind to the DNA in a non-intercalative, probably via minor groove. Molecular docking followed by semiempirical simulations indicated that these complexes showed favorable interactions with the minor groove of the double helix of ct-DNA in an A-T rich region. Thereafter, flow cytometry analysis showed that complex 2 induced apoptosis and necrosis in MCF-7 cells.

Impact of Early Passive Exercise With Cycle Ergometer on Ventilator Interaction.

BACKGROUND: Early exercise has been recommended in critically ill patients, but its impact on subject-ventilator interaction is still unclear. Therefore, the aim of this study was to evaluate the occurrence of subject-ventilator asynchrony during passive exercise in mechanically ventilated subjects. METHODS: This study included deeply sedated subjects who were under mechanical ventilation for < 72 h. Subjects were coupled to a cycle ergometer and maintained at rest for 5 min (baseline period). After this period, they started 20 min of passive exercise, followed by 10 min of rest (recovery period). The occurrence of asynchrony was monitored by the analysis of flow and airway pressure waveforms, registered throughout the protocol during the baseline, exercise, and recovery periods. Hemodynamic and respiratory parameters were registered at the end of each period. Finally, arterial blood gas analysis was performed twice, at the end of the baseline period and at the end of the recovery period. RESULTS: 8 subjects were enrolled (63.3 ± 16.7 y old, 50% male). The asynchrony index increased during exercise (median 32.1% [interquartile range (IQR) 18.6-47.6%]), compared to baseline (median 6.6% [IQR 3.9-10.4%]), returning to initial levels during the recovery period (median 2.7% [IQR 0-12.2%]). The most frequent types of asynchrony were ineffective triggering (index of 11.8% [IQR 1.2-22.5%] during exercise, compared to 2.0% [IQR 1.4-4.4%] at baseline), and insufficient flow (index of 11.7% [IQR 4.7-19.3%] during exercise, compared to 2.0% [IQR 1.1 to 3.3%] at baseline). There were no significant changes in the hemodynamic and respiratory variables. CONCLUSIONS: Early cycle ergometer passive exercise in deeply sedated subjects can worsen subject-ventilator interaction, due to ineffective triggering and insufficient flow. Adjustments in the ventilatory parameters may be necessary to avoid asynchrony during exercise.