3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo.

The amount of unfolded proteins is increased in cancer cells, leading to endoplasmic reticulum (ER) stress. Therefore, cancer cells are sensitive to drugs capable of further enhancing ER stress. Examples of such drugs include the clinically approved proteosome inhibitors bortezomib and carfilzomib. Unfortunately, the known ER stress inducers exhibit dose-limiting side effects that justify the search for better, more cancer-specific drugs of this type. Herein, we report on FeC 2, which binds to unfolded proteins prevents their further processing, thereby leading to ER stress and ROS increase in cancer cells, but not in normal cells. FeC 2 exhibits low micromolar toxicity toward human acute promyelocytic leukemia HL-60, Burkitt's lymphoma BL-2, T-cell leukemia Jurkat, ovarian carcinoma A2780, lung cancer SK-MES-1, and murine lung cancer LLC1 cells. Due to the cancer-specific mode of action, 2 is not toxic in vivo up to the dose of 147 mg/kg, does not affect normal blood and bone marrow cells at the therapeutically active dose, but strongly suppresses both primary tumor growth (confirmed in Nemeth-Kellner lymphoma and LLC1 lung cancer models of murine tumor) and spreading of metastases (LLC1).

Sugar-Bridged Fullerene Dumbbells and Their Interaction with the [10]Cycloparaphenylene Nanoring.

The synthesis and characterization of four dumbbell-shaped fullerene molecules connected by isosorbide and isomannide moieties is presented. Additionally, their electrochemical behavior and their ability to form complexes with [10]cycloparaphenylene ([10]CPP) were investigated. The cyclic voltammetry (CV) results of the fullerene dumbbells demonstrate a high electron affinity, indicating their strong interaction with electron-donating counterparts such as carbon nanorings, which possess complementary charge and shape properties. To study the thermodynamic and kinetic parameters of complexation, isothermal titration calorimetry (ITC) was employed. NMR titration experiments provided further insights into the binding stoichiometries. Two distinct approaches were utilized to create bridged structures: one based on cyclopropane and the other based on furan. Regardless of the type of linker used, all derivatives formed conventional 2 : 1 complexes denoted as [10]CPP2 ⊃C60derivative . However, the methano-dumbbell molecules exhibited distinct binding behavior, resulting in the formation of mono- and bis-pseudorotaxanes, as well as oligomers (polymers). The formation of linear polymers holds significant potential for applications in solar energy conversion processes.

A molecular Popeye: Li+@C60 and its complexes with [n]cycloparaphenylenes.

In this work, we compare for the first time the stability of [n]cycloparaphenylene ([n]CPP)-based host-guest complexes with Li+@C60 and C60 in the gas and the solution phase. Our gas-phase experiments reveal a significant increase in stability for the complexes featuring [9-12]CPP with Li+@C60. This increased interaction strength is also observed in solution. Isothermal titration calorimetry shows for the formation of [10]CPP⊃Li+@C60 a two orders of magnitude larger association constant than that for the C60 analog. Additionally, an increased binding entropy is observed. This study contributes to a better understanding of host-guest complexes between [n]CPPs and endohedral metallofullerenes at a molecular level, which is the prerequisite for future applications.

Two Rings Around One Ball: Stability and Charge Localization of [1 : 1] and [2 : 1] Complex Ions of [10]CPP and C60/70 [ *].

We investigate the gas-phase chemistry of noncovalent complexes of [10]cycloparaphenylene ([10]CPP) with C60 and C70 by means of atmospheric pressure photoionization and electrospray ionization mass spectrometry. The literature-known [1 : 1] complexes, namely [10]CPP⊃C60 and [10]CPP⊃C70 , are observed as radical cations and anions. Their stability and charge distribution are studied using energy-resolved collision-induced dissociation (ER-CID). These measurements reveal that complexes with a C70 core exhibit a greater stability and, on the other hand, that the radical cations are more stable than the respective radical anions. Regarding the charge distribution, in anionic complexes charges are exclusively located on C60 or C70 , while the charges reside on [10]CPP in the case of cationic complexes. [2 : 1] complexes of the ([10]CPP2 ⊃C60/70 )+ ⋅/- ⋅ type are observed for the first time as isolated solitary gas-phase species. Here, C60 -based [2 : 1] complexes are less stable than the respective C70 analogues. By virtue of the high stability of cationic [1 : 1] complexes, [2 : 1] complexes show a strongly reduced stability of the radical cations. DFT analyses of the minimum geometries as well as molecular dynamics calculations support the experimental data. Furthermore, our novel gas-phase [2 : 1] complexes are also found in 1,2-dichlorobenzene. Insights into the thermodynamic parameters of the binding process as well as the species distribution are derived from isothermal titration calorimetry (ITC) measurements.

Diastereoselective formation of homochiral flexible perylene bisimide cyclophanes and their hybrids with fullerenes.

Cyclophanes of different ring sizes featuring perylene-3,4:9,10-tetracarboxylic acid bisimide (PBI) linked by flexible malonates were designed, synthesized, and investigated with respect to their structural, chemical and photo-physical properties. It is predominantly the number of PBIs and their geometric arrangement, which influence dramatically their properties. For example, two-PBI containing cyclophanes reveal physico-chemical characteristics that are governed by strong co-facial π-π interactions. This is in stark contrast to cyclophanes with either three or four PBIs. Key to co-facial π-π stackings are the flexible malonate linkers, which, in turn, set up the ways and means for diastereoselectivity of the homochiral PBIs at low temperatures, on one hand. In terms of selectivity, diastereomeric (M,M)/(P,P) : (M,P)/(P,M) pairs with a ratio of approximately 10 : 1 are discernible in the 1H NMR spectra in C2D2Cl4 and a complete diastereomeric excess is found in CD2Cl2. On the other hand, symmetry-breaking charge transfer as well as charge separation at room temperature are corroborated in steady-state and time-resolved photo-physical investigations. Less favourable are co-facial π-π stackings in the three-PBI containing cyclophanes. For statistical reasons, the diastereoisomers (M,M,M)/(P,P,P) and (M,M,P)/(P,P,M) occur here in a ratio of 1 : 3. In this case, symmetry-breaking charge transfer as well as charge separation are both slowed down. The work was rounded-off by integrating next to the PBIs, for the first time, hydrophobic or hydrophilic fullerenes into the resulting cyclophanes. Our novel fullerene-PBI cyclophanes reveal unprecedented diastereoselective formation of homochiral (M,M)/(P,P) pairs exceeding the traditional host-guest approach. Hybridization with fullerenes allows us to modulate the resulting solubility, stacking, cavity and chirality, which is of tremendous interest in the field.