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[Image: see text] Mitochondrion, the powerhouse of the cells, has emerged as one of the unorthodox targets in anticancer therapy due to its involvement in several cellular functions. However, the development of small molecules for selective mitochondrial damage in cancer cells remained limited and less explored. To address this, in our work, we have synthesized a natural product inspired cyanine-based 3-methoxy pyrrole small molecule library by a concise strategy. This strategy involves Vilsmeier and Pd(0) catalyzed Suzuki cross-coupling reactions as key steps. The screening of the library members in HeLa cervical cancer cells revealed two new molecules that localized into subcellular mitochondria and damaged them. These small molecules perturbed antiapoptotic (Bcl-2/Bcl-xl) and pro-apoptotic (Bax) proteins to produce reactive oxygen species (ROS). Molecular docking studies showed that both molecules bind more tightly with the BH3 domain of Bcl-2 proteins compared to obatoclax (a pan-Bcl-2 inhibitor). These novel small molecules arrested the cell cycle in the G0/G1 phase, cleaved caspase-3/9, and finally prompted late apoptosis. This small molecule-mediated mitochondrial damage induced remarkably high cervical cancer cell death. These unique small molecules can be further explored as chemical biology tools and next-generation organelle-targeted anticancer therapy.

Donor–acceptor π-conjugated molecules with triphenylamine donor and different acceptor (H, cyano, and pyridinium) units with a double bond spacer were synthesized. These compounds exhibit bathochromic shifts in absorption and emission with an increase in the acceptor strength. Solvatochromic measurements in water reveal emitting states characterized by a polar nature with three distinct emission spectral regions from blue to red. Interestingly, binary mixtures of the stilbenes in acetonitrile and water gave white light emission. MD simulations of the admixtures reveal that the emission data directly correlate to the structural arrangements of the molecules driven by intermolecular and solvent interactions with micelle-like structural arrangements for one set and uniform homogenous mixing for the other two sets. Such a tunable emission strategy using simple structural siblings could offer great potential towards designing novel emitting systems.

Biomacromolecules rely on the precise placement of monomers to encode information for structure, function, and physiology. Efforts to emulate this complexity via the synthetic control of chemical sequence in polymers are finding success; however, there is little understanding of how to translate monomer sequence to physical material properties. Here we establish design rules for implementing this sequence-control in materials known as complex coacervates. These materials are formed by the associative phase separation of oppositely charged polyelectrolytes into polyelectrolyte dense (coacervate) and polyelectrolyte dilute (supernatant) phases. We demonstrate that patterns of charges can profoundly affect the charge–charge associations that drive this process. Furthermore, we establish the physical origin of this pattern-dependent interaction: there is a nuanced combination of structural changes in the dense coacervate phase and a 1D confinement of counterions due to patterns along polymers in the supernatant phase., Monomer sequence is an emerging tool to precisely encode information (and thus structure and function) into polymer systems. Here the authors use sequence-control in complex coacervates to understand how monomer sequence translates to physical material properties.

Two AIE active α-cyanostilbene fluorophores substituted with octyl and hexadecyl chains were synthesized and examined for their absorption and fluorescence properties. The alkoxy substitution tunes the self-assembly in water and exhibits an intensity enhanced bathochromic shift, resulting in well-defined nanospheres with the formation of nice dendrimeric structures. Monte Carlo simulations validate our experimental observations and show the greater propensity of self-assembly formation for cyanostilbene containing a hexadecyl chain compared to a derivative containing an octyl chain. The results are substantiated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and dynamic light scattering (DLS) studies. Such tunable self-assembled nanostructures seem promising for material and biological applications.

Our ability to predict the thermodynamic phase behavior of a material system is a direct reflection on our understanding of the relevant interactions. Voorn–Overbeek (VO) theory, which combines Flory–Huggins polymer mixing with Debye–Huckel electrostatics, has been used to describe the associative liquid–liquid phase separation phenomenon known as complex coacervation since the 1950s. The long-standing utility of this theory stems from its simplicity coupled with its apparent agreement with physical systems. VO theory has also served as the starting point for a large class of field theories that predict similar phase behaviors. Recent work using new hybrid simulation methods demonstrates novel coacervate-driven self-assembly is strongly affected by molecular details. Liquid state (LS) theory suggests there are fundamental reasons for this observation and that agreement between VO and experiment is fortuitous. It is hypothesized that VO/experimental matching is due to a cancellation of errors arising from ...

Oppositely charged polyelectrolytes in aqueous solution can undergo associative phase separation into a liquid-like complex coacervate phase that is polyelectrolyte-rich and an aqueous supernatant phase that is polyelectrolyte-deficient. This same complex coacervation motif can be used to drive self-assembly of block copolyelectrolytes via electrostatic interactions and can be controlled using e.g. ionic strength, pH, temperature, and polymer architecture. While there has been a large amount of research studying this self-assembly, the ability of theory to accurately capture the disparate length scales that govern the appropriate physics is limited. This is especially true when the coacervates have a high charge density; examples include biopolymers such as heparin or DNA as well as synthetic polymers such as poly(styrenesulfonate) or poly(acrylic acid). We incorporate molecular-level Monte Carlo simulations into single chain in mean field simulations, leading to a multiscale, coarse-grained description o...

Reduced activity of enzymes upon immobilization is a major challenge for the industrial use of enzymes. Enzyme-surface interactions and interactions between the immobilized enzymes are thought of as primary reasons for the reduced activity. In the current paper, we study the thermal and structural stability of proteins on a patterned hydrophobic surface in the framework of a hydrophobic-polar lattice model. Our results indicate that, while a homogeneous hydrophobic surface denatures the proteins, carefully patterned surfaces can dramatically increase the stability of adsorbed proteins. The size, shape, and the distance between surface patterns play a significant role in determining the stability of proteins. When the spacing between the patterns is large, maximum stability is observed when the surface pattern is complementary to the exposed hydrophobic domain of the protein, while at smaller spacing, patterns with lower hydrophobicity stabilize the protein more compared to the complementary pattern. The findings from the paper can be rationalized to design novel enzyme-specific surfaces for immobilization with enhanced enzymatic activity.

Relative surface affinity between polymers and colloids is leveraged in many applications like filtration, adhesion, bio-sensing, etc. The surface affinity is governed by both enthalpic (relative interactions between the species and surface) and entropic (excluded volume) effects. Neglecting enthalpic effects, i.e. for purely athermal systems, entropy is the only driving force that controls the surface affinity of the species in a binary or multi-component mixture. Many intensive (relative size of colloids, chain length, equilibrium bond angle, chain flexibility) and extensive (confinement, temperature) factors can dramatically change the entropy of the system and thus enhance or decrease the surface affinities of the constituent species. In this article, we use coarse grained metropolis Monte Carlo simulations to delineate the role of these factors in entropic surface segregation in a binary mixture of polymers and colloids. At low number densities, excluded volume effects are negligible and we do not observe any entropic driven surface segregation. Therefore our system of interest is binary polymer–colloid mixtures at moderate to high number densities where excluded volume effects are predominant. Our results indicate that for flexible polymer chains, the surface is always enriched with colloids compared to polymers and this effect is enhanced for longer polymer chains. The configurational entropy of the flexible polymers is significantly reduced near the surface and therefore they prefer to stay in the bulk (away from the surface). However this behavior can be completely reversed by introducing a large degree of confinement and making the chains relatively rigid (less flexible). Our results show that polymer segregation of long stiff chains in slit pore geometry is driven by nematization near the surface while looping of polymers is observed under a large degree of confinement. We observe that for longer polymer chains with an equilibrium bond angle (θ = π), both confinement and chain stiffness enhance the surface segregation of polymers relative to colloids. However, the segregation behavior within a confinement is dependent on the polymer chain length. The surface segregation of polymers is dramatically decreased for chains with equilibrium bond angles independent of chain length and flexibility due to excluded volume effects and inefficient packing near the surface.

Aggregation-induced-emission luminogens (AIEgens) have gained considerable attention as interesting tools for several biomedical applications, especially for bioimaging due to their brightness and photostability. Numerous AIEgens have been developed for lighting up the subcellular organelles to understand their forms and functions not only healthy but also unhealthy states, such as in cancer cells. However, there is lack of easily synthesizable, biocompatible small molecules for illuminating mitochondria (powerhouses) inside cells. To address this issue, an easy and short synthesis of new biocompatible hydrazide-hydrazone-based small molecules with remarkable aggregation-induced emission (AIE) properties is described. These small-molecule AIEgens showed hitherto unobserved AIE properties due to dual intramolecular H-bonding confirmed by theoretical calculation, pH- and temperature-dependent fluorescence and X-ray crystallographic studies. Confocal microscopy showed that these AIEgens were internalized into the HeLa cervical cancer cells without showing any cytotoxicity. One of the AIEgens was tagged with a triphenylphosphine (TPP) moiety, which successfully localized in the mitochondria of HeLa cells in a selective way compared to L929 noncancerous fibroblast cells. These unique hydrazide-hydrazone-based biocompatible AIEgens can serve as powerful tools to illuminate multiple subcellular organelles to elucidate their forms and functions in cancer cells for next-generation biomedical applications.

A simple fluorophore bearing a diethylaminocoumarin donor and a pyridinium acceptor was synthesized and utilized for the ultra-sensitive detection of heparin. The synthesized dicationic push-pull coumarin derivative emits strongly in the red-region (665 nm) and detects nanomolar concentrations (14.8 nM to 148 nM) of heparin in HEPES buffer and FBS serum solutions. The dication exhibits excellent fluorescence selectivity and sensitivity towards heparin over its analogues such as chondroitin 4-sulfate (CS), hyaluronic acid (HA) and dextran. This fluorescence assay is a convenient, sensitive method for monitoring heparin levels in biological samples. These findings were confirmed using coarse-grained Monte Carlo simulations, which provide us with a rationale for the selective binding of heparin.