Ferrocene containing N-heterocyclic carbene (NHC) ligated gold(I) complexes of the type [Au(NHC)2]+ were prepared and found to be capable of regulating the formation of reactive oxygen species (ROS) via multiple mechanisms. Single crystal X-ray analysis of bis(1-(ferrocenylmethyl)-3-mesitylimidazol-2-ylidene)-gold(I) chloride (5) and bis(1,3-di(ferrocenylmethyl)imidazol-2-ylidene)-gold(I) chloride (6) revealed a quasi-liner geometry around the gold(I) centers, (i.e., the C–Au–C bond angle were measured to be ~177° and all the Au–Ccarbene bonds distances were in the range of 2.00 (7) – 2.03 (1) Å). A series of cell studies indicated that cell proliferation inhibition and ROS generation were directly proportional to amount of ferrocene contained within the [Au(NHC)2]+ complexes (IC50 of 6 < 5 < bis(1-benzyl-3-mesitylimidazol-2-ylidene)-gold(I) chloride (4)). Complexes 4–6 were also confirmed to inhibit thioredoxin reductase as inferred from lipoate reduction assays and increase chelatable intracellular zinc concentrations. RNA microarray gene expression assays revealed that 6 induces endoplasmic reticulum stress response pathways as a result of ROS increase.

Herein, we report a simple and rational approach to the design of a targeted therapy (i.e., complex 1) whose mechanism of action involves targeting a single cancer relevant pathway via two independent mechanisms.

Water‐soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co‐incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of PtIV to PtII promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the PtIV species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer‐selective enhancement in the cytotoxicity of PtIV prodrugs.

Water soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt(IV) prodrugs.

In this study the rational design, synthesis, and anticancer activity of quinoline-derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp(3) -C-H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4-trifluoro-3-hydroxy-3-(quinolin-2-ylmethyl)butanoate (1), 2-benzyl-1,1,1-trifluoro-3-(quinolin-2-yl)propan-2-ol (2), and trifluoro-3-(isoquinolin-1-yl)-2-(thiophen-2-yl)propan-2-ol (3). Compounds 2 and 3 were found to be more toxic than compound 1; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2, with an LC50 value of 14.14 μm, has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents.

Tin dioxide nanofibers (SnDNFs) are small fibers that have many applications. Tin dioxide nanofibers can be used in cosmetics, solar cells, toxic gas release sensors, and air pollution control. To date there have been few studies on the cytotoxicity of SnDNFs. The goal of this research is to determine if electrospun SnDNFs are toxic in a lung cancer cell line (A549). Considering the nano-scale size of the fibers, they can easily be inhaled and enter the pulmonary system and cause toxic effects in the lung. Occupational exposure to SnDNFs has been linked to pulmonary disease, making the A549 cell line important in this study. Nanofiber toxicity can vary based upon the characteristics of the fibers. Smaller nanofibers have been shown to have more toxic effects than their larger counterparts. The synthesized SnDNFs were characterized using SEM, Raman spectroscopy, and powder X-ray diffractometer (PXRD). SEM images showed the fibers to be 200-300 nm in diameter. Raman spectroscopy and PXRD indicated that the fibers were in the rutile phase. After quantifying the SnDNFs, the fibers were introduced to A549 cells at concentrations ranging from 0.02-500 µg mL and incubated at 37°C. These cells were quantified with the MTT assay to measure cell proliferation (IC = 0.02 mg mL), while lactate dehydrogenase (LDH) leakage was used to determine cytotoxicity, and apoptosis assays to assess the mechanism of cell death. Increasing concentration of SnDNF generated a consequential decrease in cell proliferation and viability. The percent cytotoxicity of SnDNF was not significantly changed at the various concentrations and time frames. In order to gain additional insight about the mechanism of cytotoxicity of SnDNFs, genes with links to inflammation and apoptosis were evaluated and found to be over-expressed in treated cells. At the concentrations of SnDNF examined, SnDNF was mildly toxic to the A549 cells.

Antitumor Agents In their Communication on page 12626 ff., Z. H. Siddik, J. L. Sessler, and co‐workers show that in the presence of vitamin C, gadolinium texaphyrin accelerates the reduction of PtIV prodrugs in vitro to give the active PtII species.

Tumortherapeutika In ihrer Zuschrift auf S. 12816 ff. zeigen Z. H. Siddik, J. L. Sessler und Mitarbeiter, dass Gadoliniumtexaphyrin in Gegenwart von Vitamin C die Reduktion von PtIV‐Prodrugs zu den aktiven PtII‐Spezies in vitro beschleunigt.