Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.     

Tracking the Interplay between Bound Peptide and the Lid Domain of DnaK,Using Molecular Dynamics

Hsp70 chaperones consist of two functional domains: the 44 kDa Nucleotide Binding Domain (NBD), that binds and hydrolyses ATP, and the 26 kDa Substrate Binding Domain (SBD), which binds unfolded proteins and reactivates them, utilizing energy obtained from nucleotide hydrolysis. The structure of the SBD of the bacterial Hsp70, DnaK, consists of two sub-domains: A β-sandwich part containing the hydrophobic cavity to which the hepta-peptide NRLLLTG (NR) is bound, and a segment made of 5 α-helices, called the “lid” that caps the top of the β-sandwich domain. In the present study we used the Escherichia coli Hsp70, DnaK, as a model for Hsp70 proteins, focusing on its SBD domain, examining the changes in the lid conformation. We deliberately decoupled the NBD from the SBD, limiting the study to the structure of the SBD section, with an emphasis on the interaction between the charges of the peptide with the residues located in the lid. Molecular dynamics simulations of the complex revealed significant mobility within the lid structure; as the structure was released from the forces operating during the crystallization process, the two terminal helices established a contact with the positive charge at the tip of the peptide. This contact is manifested only in the presence of electrostatic attraction. The observed internal motions within the lid provide a molecular role for the function of this sub-domain during the reaction cycle of Hsp 70 chaperones.     

Low threshold and low dispersion MOCVD/LPE buried-heterostructure GaAs/GaAlAs lasers

We report on the first MOCVD/LPE buried-heterostructure lasers realised using a simple LPE burying process, leading to low thresholds and little dispersion in device characteristics.     

Metalorganic InP and Inx Ga1-x,Asy P1-y,on InP epitaxy at atmospheric pressure

We present a procedure for the MOVPE of InP as simple as the one currently used for GaAs. InP and InGaAsP alloys are grown on InP substrates using trimethy1indium (TMI), phosphine, trimethylgallium (TMG) and arsine. The choice of carrier gas is important ; a mixture of hydrogen and nitrogen allowed us to grow uniform layers over large areas at atmospheric pressure, without pyrolizing the phosphine or separating the input reactants. Preliminary characterization results are presented. Most information contained in this paper was presented at the 1983 Electron Materials Conference as paper Cl.     

Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver

The metabolism of imipramine by human liver microsomes was examined using a combination of five strategies. Human hepatic microsomes produced N-desmethylimipramine (84%), 2-hydroxyimipramine (10%), and 10-hydroxyimipramine (6%). Preincubation of human hepatocytes in culture with beta-naphthoflavone and macrolides exclusively induced the formation of desmethylimpramine (552%, p < 0.05, and 234%, p < 0.003, respectively). Correlations were obtained between rates of imipramine demethylation and cytochrome P-450 (P-450) 1A2 (r = 0.88, p < 0.001) and P-450 3A (r = 0.80, p < 0.02) concentrations in human liver microsomal preparations from 13 different subjects. Anti-P-450 1A2 and anti-P-450 3A antibodies selectively inhibited N-demethylation (80% and 60%, respectively). N-Demethylation was completely inhibited when anti-1A2 and anti-3A were added simultaneously. Kinetic studies with human microsomes confirm the contribution of two different enzymes in the N-demethylation. The Km of 1A2 was similar to the high affinity Km in human liver microsomes, whereas the Km of 3A was similar to the low affinity Km in human liver microsomes. P-450 1A2 was apparently more efficient than 3A4 (lower Km and higher Vmax) but was expressed in much lower concentration. Human P-450s 1A2 and 3A4 expressed in yeast efficiently produced desmethylimipramine. These results suggest that P-450 1A2 and P-450 3A4 are the major enzymes involved in imipramine N-demethylation in human hepatic microsomes. Similar experiments were conducted using P-450 2D6, and they confirmed that P-450 2D6 catalyzes imipramine 2-hydroxylation. Interindividual variations in 3A4 hepatic content may explain the large variations in imipramine blood levels observed after uniform dosages and thus may explain the variations in clinical efficacy. Caution might be advised in the clinical use of tricyclic antidepressants when drugs are also administered that induce or inhibit P-450s 3A4 and 1A2.     

Modifying Crystallinity,Morphology, and Photophysical Properties of Carbon Nitride by Using Crystals as Reactants

Here we show a general method to improve the crystallinity of carbon nitride nanosheets by using melamine crystals as reactants for the high temperature synthesis. Additionally, the crystals were calcined in a sealed ampoule, which provides a pressurized environment, yielding crystalline carbon nitride nanosheets that display altered morphology and photophysical properties compared to the reference materials. Electronic microscopy, optical and photoelectrochemical measurements prove the modifications of parameters such like band structure, charge recombination or inter-layer distance. The new growth strategy presented here opens many opportunities for the design of crystalline materials with tailored properties for different applications.     

Open‐Shell Donor–Acceptor Conjugated Polymers with High Electrical Conductivity

Conductive polymers largely derive their electronic functionality from chemical doping, processes by which redox and charge‐transfer reactions form mobile carriers. While decades of research have demonstrated fundamentally new technologies that merge the unique functionality of these materials with the chemical versatility of macromolecules, doping and the resultant material properties are not ideal for many applications. Here, it is demonstrated that open‐shell conjugated polymers comprised of alternating cyclopentadithiophene and thiadiazoloquinoxaline units can achieve high electrical conductivities in their native “undoped” form. Spectroscopic, electrochemical, electron paramagnetic resonance, and magnetic susceptibility measurements demonstrate that this donor–acceptor architecture promotes very narrow bandgaps, strong electronic correlations, high‐spin ground states, and long‐range π‐delocalization. A comparative study of structural variants and processing methodologies demonstrates that the conductivity can be tuned up to 8.18 S cm^?1. This exceeds other neutral narrow bandgap conjugated polymers, many doped polymers, radical conductors, and is comparable to commercial grades of poly(styrene‐sulfonate)‐doped poly(3,4‐ethylenedioxythiophene). X‐ray and morphological studies trace the high conductivity to rigid backbone conformations emanating from strong π‐interactions and long‐range ordered structures formed through self‐organization that lead to a network of delocalized open‐shell sites in electronic communication. The results offer a new platform for the transport of charge in molecular systems.