This study was performed to investigate the herb-drug interactions (HDIs) of citrus herbs (CHs), which was inspired by the "grapefruit (GF) juice effect". Based on network analysis, a total of 249 components in GF and 159 compounds in CHs exhibited great potential as active ingredients. Moreover, 360 GF-related genes, 422 CH-related genes, and 111 genes associated with drug transport and metabolism were collected, while 25 and 26 overlapping genes were identified. In compound-target networks, the degrees of naringenin, isopimpinellin, apigenin, sinensetin, and isoimperatorin were higher, and the results of protein-protein interaction indicated the hub role of UGT1A1 and CYP3A4. Conventional drugs such as erlotinib, nilotinib, tamoxifen, theophylline, venlafaxine, and verapamil were associated with GF and CHs via multiple drug transporters and drug-metabolizing enzymes. Remarkably, GF and CHs shared 48 potential active compounds, among which naringenin, tangeretin, nobiletin, and apigenin possessed more interactions with targets. Drug metabolism by cytochrome P450 stood out in the mutual mechanism of GF and CHs. Molecular docking was utilized to elevate the protein-ligand binding potential of naringenin, tangeretin, nobiletin, and apigenin with UGT1A1 and CYP3A4. Furthermore, in vitro experiments demonstrated their regulating effect. Overall, this approach provided predictions on the HDIs of CHs, and they were tentatively verified through molecular docking and cell tests. Moreover, there is a demand for clinical and experimental evidence to support the prediction.

Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best K i value of 1.9 nM for PRL76V, whereas the other three inhibitors had K i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PRL76V were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.

Flavonoids are natural polyphenolic compounds with myriad biological activities and potential as prophylactic and therapeutic agents. However, poor aqueous solubility and low bioavailability have limited the clinical utility of flavonoids, suggesting that drug delivery systems (DDSs) may improve their clinical relevance. Therefore, loading of a representative flavonoid (i.e., myricetin) into a diblock, polymeric nanoparticle carrier (NPC) DDS with a cationic corona and hydrophobic core was investigated. Absorbance and fluorescence spectroscopy results revealed association constants and standard Gibbs free energy values that align with previously reported values (K a = ∼1-3 × 104 M-1; ΔG° = -5.4 to -6.0 kcal mol-1), suggesting that NPCs load myricetin via electrostatic interactions. The zeta potential and gel electrophoresis analysis confirmed this loading mechanism and indicated that NPCs improve myricetin solubility >25-fold compared to myricetin alone. Finally, the dual-drug loading of NPCs was tested using a combination of myricetin and a hydrophobic drug (i.e., farnesol). Electrostatic loading of NPCs with myricetin at concentrations ≤1.2 mM did not affect NPC core loading and release of farnesol, thus demonstrating a novel formulation strategy for the dual-drug-loaded NPC. These findings offer key insights into the NPC DDS design that may enhance the clinical relevance of flavonoid-based therapeutic approaches.

Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG). The highly cross-linked heptapeptide aglycon structure of vancomycin is the d-Ala-d-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus-modified vancomycin derivatives: desleucyl-vancomycin, vancomycinNtoC, and vancomycinSar, binding to a PG unit of the sequence l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala with an intact pentaglycine bridge structure attached to the bridge link of l-Lys were carried out. Glycopeptide-PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide-PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the d-Ala-d-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide-PG binding interactions.

β-cyclodextrin (β-CD) forms a host-guest inclusion complex with many organic and amphiphilic compounds found in pharmaceutical, textile, cosmetic, food, and personal care systems. Therefore, grafting of β-CD onto a cellulose nanocrystal (CNC) offers a possible strategy to use functionalized CNC to complex with surface-active molecules. We have successfully grafted β-CD onto CNCs in a stepwise manner using cyanuric chloride as the linker. The structure of β-CD-grafted CNC (CNC-CD) was characterized by UV-vis and Fourier-transform infrared spectroscopy, and the grafting ratio of β-CD was determined by the phenolphthalein inclusion protocol. Ionic surfactants induced the aggregation of CNC-CDs by forming inclusion complexes with β-CDs on the surface of CNC. The interactions of amphiphilic compounds with CNC-CD were examined by surface tensiometry, conductometric and potentiometric titration, and isothermal titration calorimetry. Mechanisms describing the complex formation between surfactants and CNC-CD were proposed, where an improved understanding of CD interactions with surfactants and lipids would enable better strategies for drug encapsulation and delivery with CDs.

An integrated and controlled migration of leukocytes is necessary for the legitimate functioning and maintenance of the immune system. Chemokines and their receptors play a decisive role in regulating the leukocyte migration to the site of inflammation, a phenomena often referred to as chemotaxis. Chemokines and their receptors have become significant targets for therapeutic intervention considering their potential to regulate the immune system. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a preeminent member of CC chemokine family that facilitates crucial roles by orchestrating the recruitment of monocytes into inflamed tissues. Baicalin (BA), a major bioactive flavonoid, has been reported to attenuate chemokine-regulated leukocyte trafficking. However, no molecular details pertaining to its direct binding to chemokine(s)/receptor(s) are available till date. In the current study, using an array of monomers/dimers of human and murine CCL2 orthologs (hCCL2/mCCL2), we have shown that BA binds to the CCL2 protein specifically with nanomolar affinity (K d = 270 ± 20 nM). NMR-based studies established that BA binds CCL2 in a specific pocket involving the N-terminal, β1- and β3-sheets. Docking studies suggested that the residues T16, N17, R18, I20, R24, K49, E50, I51, and C52 are majorly involved in complex formation through a combination of H-bonds and hydrophobic interactions. As the residues R18, R24, and K49 of hCCL2 are crucial determinants of monocyte trafficking through receptor/glycosaminoglycans (GAG) binding in CCL2 human/murine orthologs, we propose that baicalin engaging these residues in complex formation will result in attenuation of CCL2 binding to the receptor/GAGs, thus inhibiting the chemokine-regulated leukocyte trafficking.

Interactions between charges play a role in protein stability and contribute to the energetics of binding between various charged ligands. Ionic surfactants are charged molecules, whose interactions with proteins are still rather poorly understood despite their wide applications. Here, we show by isothermal titration calorimetry that cationic alkylammonium surfactants bind to negatively charged polyaspartate and polyglutamate homopolymers stoichiometrically, i.e., one surfactant molecule per charged amino acid. Similarly, negatively charged alkyl sulfates (e.g., sodium dodecyl sulfate) and alkane sulfonates bind stoichiometrically to positively charged polylysine, polyornithine, and polyarginine homopolymers. In these reactions, the interacting counterparts form ion pairs and the resulting electrostatically neutral complex coprecipitates from solution. The enthalpies and heat capacities are determined for various pairs of ionic surfactants and charged amino acid homopolymers. These results show the energetic contributions of ionic headgroups and the CH2 group to surfactant interactions with proteins.

Peptide nanoassemblies have garnered remarkable importance in the development of novel nanoscale biomaterials for drug delivery into tumor cells. Taking advantage of receptor mediated recognition of two known peptides, angiopep-2 (TFFYGGSRGKRNNFKTEEY) and A-COOP-K (ACGLSGLC10 VAK) that bind to the over-expressed receptors low density lipoprotein (LRP-1) and fatty acid binding protein (FABP3) respectively, we have developed new peptide conjugates by combining the anti-inflammatory, antitumor compound azelaic acid with angiopep-2, which efficiently self-assembled into nanofibers. Those nanofibers were then functionalized with the A-COOP-K sequence and formed supramolecular hierarchical structures that were found to entrap the chemotherapeutic drug doxorubicin efficaciously. Furthermore, the nanoassemblies were found to release the drug in a dose-dependent manner and showed a stepwise increase over a period of 2 weeks under acidic conditions. Two cell lines (U-87-MG and U-138-MG) were utilized as models for glioblastoma cells grown in the presence of serum and under serum-free conditions to mimic the growth conditions of natural tumors. The drug entrapped assemblies were found to inhibit the cell proliferation of both U-87 and U-138MG glioblastoma cells. Three dimensional spheroids of different sizes were grown to mimic the tumors and evaluate the efficacy of drug release and internalization. Our results indicated that the nanoassemblies were found to have higher internalization of DOX and were well-spread throughout the spheroids grown, particularly under serum-free conditions. The nanoassemblies also displayed blood-brain barrier penetration when tested with a multicellular in vitro model. Such self-assembled nanostructures with targeting ability may provide a suitable platform for the development of new peptide-based biomaterials that can provide more insights about the mechanistic approach for drug delivery for not only 2D cell cultures but also 3D tumoroids that mimic the tumor microenvironments.

We report the mechanism of the concentration-dependent self-assembly of a tetrapeptide. Peptide Boc-Trp-Leu-Trp-Leu-OMe self-assembles to form discrete nanospheres at a low concentration. Tryptophan side chains point outwards of the nanospheres while leucine side chains point towards the core of the nanospheres. The nanospheres fuse together to become microspheres with the increase in the peptide concentration. At higher concentrations of the peptide, the microspheres start clustering. This is stabilized by the aromatic interactions between the side chains of the tryptophan residues that cover the outer surface of the peptide microspheres. In addition to behaving like the conventional hollow sphere-based drug delivery vehicles which entraps the drug and performs stimuli-responsive release, this prototype can interact, stabilize, and intercalate hydrophobic dye carboxyfluorescein and anti-cancer drug curcumin even on the surface through aromatic interactions. The dye/drug can be released in acidic pH and in the presence of physiologically relevant ions such as potassium.

2,2,2-Trichloroethanol (TCE) is the active form of the sedative hypnotic drug chloral hydrate, one of the oldest sleep medications in the market. Understanding of TCE's action mechanisms to its many targets, particularly within the ion channel family, could benefit from the state-of-the-art computational molecular studies. In this direction, we employed de novo modeling aided by the force field toolkit to develop CHARMM36-compatible TCE parameters. The classical potential energy function was calibrated targeting molecular conformations, local interactions with water molecules, and liquid bulk properties. Reference data comes from both tabulated thermodynamic properties and ab initio calculations at the MP2 level. TCE solvation free energy calculations in water and oil reproduce a lipophilic, yet nonhydrophobic, behavior. Indeed, the potential mean force profile for TCE partition through the phospholipid bilayer reveals the sedative's preference for the interfacial region. The calculated partition coefficient also matches experimental measures. Further validation of the proposed parameters is supported by the model's ability to recapitulate quenching experiments demonstrating TCE binding to bovine serum albumin.

Despite the huge and efficient functionalities of reduced graphene oxide (RGO) for bioengineering applications, the use of harsh chemicals and unfavorable techniques in their production remains a major challenge. Microbial production of reduced graphene oxide (RGO) using specific bacterial strains has gained interest as a sustainable and efficient method. The reduction of GO to RGO by selected bacterial strains was achieved through their enzymatic activities and resulted in the removal of oxygen functional groups from GO, leading to the formation of RGO with enhanced structural integrity. The use of microorganisms offers a sustainable approach, utilizing renewable carbon sources and mild reaction conditions. This study investigates the production of RGO using three different bacterial strains: Lactococcus lactis (L. Lactis), Lactobacillus plantarum (L. plantarum), and Escherichia coli (E. coli) and evaluates its toxicity for safe utilization. The aim is to assess the quality of the produced RGO and evaluate its toxicity for potential applications. Thus, this study focused on the microbial production of reduced graphene oxides well as the investigation of their cellular interactions. Graphite-derived graphene oxide was used as a starting material and microbially reduced GO products were characterized using the FTIR, Raman, XRD, TGA, and XPS methods to determine their physical and chemical properties. FTIR shows that the epoxy and some of the alkoxy and carboxyl functional groups were reduced by E. coli and L. lactis, whereas the alkoxy groups were mostly reduced by L. plantarum. The ID/IG ratio from Raman spectra was found as 2.41 for GO. A substantial decrease in the ratio as well as defects was observed as 1.26, 1.35, and 1.46 for ERGO, LLRGO, and LPRGO after microbial reduction. The XRD analysis also showed a significant reduction in the interlayer spacing of the GO from 0.89 to 0.34 nm for all the reduced graphene oxides. TGA results showed that reduction of GO with L. lactis provided more reduction than other bacteria and formed a structure closer to graphene. Similarly, analysis with XPS showed that L lactis provides the most effective reduction with a C/O ratio of 3.70. In the XPS results obtained with all bacteria, it was observed that the C/O ratio increased because of the microbial reduction. Toxicity evaluations were performed to assess the biocompatibility and safety of the produced RGO. Cell viability assays were conducted using DLD-1 and CHO cell lines to determine the potential cytotoxic effects of RGO produced by each bacterial strain. Additionally, apoptotic, and necrotic responses were examined to understand the cellular mechanisms affected by RGO exposure. The results indicated that all the RGOs have concentration-dependent cytotoxicity. A significant amount of cell viability of DLD-1 cells was observed for L. lactis reduced graphene oxide. However, the highest cell viability of CHO cells was observed for L. plantarum reduced graphene oxide. All reduced graphene oxides have low apoptotic and necrotic responses in both cell lines. These findings highlight the importance of considering the specific bacterial strain used in RGO production as it can influence the toxicity and cellular response of the resulting RGO. The toxicity and cellular response to the final RGO can be affected by the particular bacterial strain that is employed to produce it. This information will help to ensure that RGO is used safely in a variety of applications, including tissue engineering, drug delivery systems, and biosensors, where comprehension of its toxicity profile is essential.

Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-β (Aβ) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aβ probes, as well as those between the probe and the Aβ aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aβ probes. We synthesized a series of five fluorescent Aβ probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aβ, Aβ40 and Aβ42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δν = 797 cm-1) to the Aβ40 and Aβ42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aβ aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aβ42 and Aβ40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aβ species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aβ aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aβ peptides and the probe molecule.

Nanoparticles made of amphiphilic block copolymers are commonly used in the preparation of nano-sized drug delivery systems. Poly(styrene)-block -poly(acrylic acid) (PS-PAA) copolymers have been proposed for drug delivery purposes; however, the drug loading capacity and cytotoxicity of PS-PAA nanoparticles are still not fully recognized. Herein, we investigated the accumulation of a model hydrophobic drug, curcumin, and its spatial distribution inside the PS-PAA nanoparticles. Experimental methods and atomistic molecular dynamics simulations were used to understand the molecular structure of the PS core and how curcumin molecules interact and organize within the PS matrix. The hydrophobic core of the PS-PAA nanoparticles consists of adhering individually coiled polymeric chains and is compact enough to prevent post-incorporation of curcumin. However, the drug has a good affinity for the PS matrix and can be efficiently enclosed in the PS-PAA nanoparticles at the formation stage. At low concentrations, curcumin is evenly distributed in the PS core, while its aggregates were observed above ca. 2 wt %. The nanoparticles were found to have relatively low cytotoxicity to human skin fibroblasts, and the presence of curcumin further increased their biocompatibility. Our work provides a detailed description of the interactions between a hydrophobic drug and PS-PAA nanoparticles and information on the biocompatibility of these anionic nanostructures which may be relevant to the development of amphiphilic copolymer-based drug delivery systems.

Here, we present how replacing the usual inorganic counter ion with a pharmaceutically active aromatic one can greatly affect the interfacial as well as bulk properties of ionic liquids (ILs). We have synthesized a series of novel drug-based ILs, namely, 1-alkyl-3-methylimidazolium diclofenate ([C n mim][DF]; n = 6, 8, 10, 12, and 14) abbreviated as DF-ILs, wherein DF- is a well-recognized analgesic and nonsteroidal anti-inflammatory drug. We show strong synergistic interactions between C n mim+ and aromatic DF- attributed to reduced electrostatic repulsions and increased hydrophobicity from their incorporation, reflecting a 300-fold smaller critical aggregation concentration than that of their Cl- analogue [C n mim][Cl]. Interfacial properties for such strongly associating systems are discussed and clearly established to have remarkably improved properties than those of their Cl- analogues. The decreasing polarity of the cybotactic region of pyrene with increase in the chain length "n" indicates an increased extent of packing of cationic head groups in the Stern layer. DF- ion seems to play a vital role in the formation of the resulting aggregates, as probed by small angle neutron scattering and transmission electron microscopy. The thermodynamical insights of the aggregation process have been studied using isothermal titration calorimetry and temperature-dependent conductivity experiments. Unilamellar vesicles are formed at extremely low concentration, and also it is the first report that puts into picture the formation of vesicles for [C6mim][DF] with such a short chain.

DNA binding investigations are critical for designing better pharmaceutical compounds since the binding of a compound to dsDNA in the minor groove is critical in drug discovery. Although only one in vitro study on the DNA binding mode of apigenin (APG) has been conducted, there have been no electrochemical and theoretical studies reported. We hereby report the mechanism of binding interaction of APG and a new class of sulfonamide-modified flavonoids, apigenin disulfonamide (ADSAM) and apigenin trisulfonamide (ATSAM), with deoxyribonucleic acid (DNA). This study was conducted using multispectroscopic instrumentation techniques, which include UV-vis absorption, thermal denaturation, fluorescence, and Fourier transform infrared (FTIR) spectroscopy, and electrochemical and viscosity measurement methods. Also, molecular docking studies were conducted at room temperature under physiological conditions (pH 7.4). The molecular docking studies showed that, in all cases, the lowest energy docking poses bind to the minor groove of DNA and the apigenin-DNA complex was stabilized by several hydrogen bonds. Also, π-sulfur interactions played a role in the stabilization of the ADSAM-DNA and ATSAM-DNA complexes. The binding affinities of the lowest energy docking pose (schematic diagram of table of content (TOC)) of APG-DNA, ADSAM-DNA, and ATSAM-DNA complexes were found to be -8.2, -8.5, and -8.4 kcal mol-1, respectively. The electrochemical binding constants K b were determined to be (1.05 × 105) ± 0.04, (0.47 × 105) ± 0.02, and (8.13 × 105) ± 0.03 for APG, ADSAM, and ATSAM, respectively (all of the tests were run in triplicate and expressed as the mean and standard deviation (SD)). The K b constants calculated for APG, ADSAM, and ATSAM are in harmony for all techniques. As a result of the incorporation of dimethylsulfamate groups into the APG structure, in the ADSAM-dsDNA and ATSAM-dsDNA complexes, in addition to hydrogen bonds, π-sulfur interactions have also contributed to the stabilization of the ligand-DNA complexes. This work provides new insights that could lead to the development of prospective drugs and vaccines.

Drug repositioning is the identification of interactions between drugs and target proteins in pharmaceutical sciences. Traditional large-scale validation through chemical experiments is time-consuming and expensive, while drug repositioning can drastically decrease the cost and duration taken by traditional drug development. With the rapid advancement of high-throughput technologies and the explosion of various biological and medical data, computational drug repositioning methods have been used to systematically identify potential drug-target interactions. Some of them are based on a particular class of machine learning algorithms called kernel methods. In this paper, we propose a new machine learning prediction method combining multiple kernels into a tripartite heterogeneous drug-target-disease interaction spaces in order to integrate multiple sources of biological information simultaneously. This novel network algorithm extends the traditional drug-target interaction bipartite graph to the third disease layer. Meanwhile, Gaussian kernel functions on heterogeneous networks and the regularized least square method of the Kronecker product are used to predict new drug-target interactions. The values of AUPR (area under the precision-recall curve) and AUC (the area under the receiver operating characteristic curve) of the proposed algorithm are significantly improved. Especially, the AUC values are improved to 0.99, 0.99, 0.97, and 0.96 on four benchmark data sets. These experimental results substantiate that the network topology can be used for predicting drug-target interactions.

The binding site of the macrolides laulimalide and peloruside A, which is different from that of the clinically useful drugs paclitaxel/taxol and ixabepilone (tax site), is known to be between two adjacent β-tubulin units (ext site). Here, we report our study of the binding of these molecules to an α1β1/α2β2-tubulin "tetramer" model. AutoDock 4.2.6//AutoDock Vina dockings predicted that the affinities of laulimalide and peloruside A for the tax site are quite similar to those for the ext site. However, molecular dynamics (MD) simulations indicated that only when these two ligands are located at the ext site, there are contacts that help stabilize the system, favoring the β1/β2 interactions. The binding affinity of laulimalide for this site is stronger than that of peloruside A, but this is compensated for by additional β1/β2 contacts that are induced by peloruside A. MD studies also suggested that epothilones at the tax site and either laulimalide or peloruside A at the ext site cause similar stabilizing effects (mainly linking the M-loop of β1 and loop H1-B2 of β2). In a "hexamer" model (3 units of αβ-tubulin), the effects are confirmed. Metadynamics simulations of laulimalide and peloruside A, which are reported for the first time, suggest that peloruside A produces a stronger change in the M-loop, which explains the stabilization of the β1/β2 interaction.

The bioderived platform molecule levoglucosenone (LGO, 1) and its readily prepared pseudoenantiomer (iso-LGO, 2) have each been subjected to α-iodination reactions with the product halides then being engaged in palladium-catalyzed Ullmann cross-coupling reactions with various bromonitropyridines. The corresponding α-pyridinylated derivatives such as 11 and 24, respectively, are produced as a result. Biological screening of such products reveals that certain of them display potent and selective antimicrobial and/or cytotoxic properties. In contrast, the azaindoles obtained by reductive cyclization of compounds such as 11 and 12 are essentially inactive in these respects. Preliminary mode-of-action studies are reported.

The visible fluorescent chromophoric moiety present in the water-soluble photoactive yellow protein (PYP) of Ectothiorhodospira halophila is p-hydroxycinnamic acid linked to the cysteine residue (Cys-69) by a thioester bond and it controls the key photoinduced biological processes of the host organism. In the present work, we have synthesized and characterized three structurally different thiophenyl esters [viz., p-hydroxycinnamic-thiophenyl ester (1), p-N,N-dimethylaminocinnamic-thiophenyl ester (2), and S-phenyl-3-(4-chlorophenyl)-3-(phenylthio)propanethioate (3)] in addition to a novel (to the best of our knowledge) stilbene-type olefinic compound, N1,N1,N2,N2-tetramethyl-1,2-bis(phenylthio)ethene-1,2-diamine (4), under the same reaction condition. All of these four compounds showed characteristic and distinguishable chromophoric/fluorophoric behavior in ethanol and also at pH 7.4. However, we have observed that the intrinsic chromophoric/fluorophoric activities of (1) and (2) were greatly influenced during their interactions with calf-thymus DNA, studied by a range of spectroscopic and physicochemical measurements. We have also applied density functional theory [B3LYP, 6-311G+(d,p)]-based method to get optimized structures of (1) and (2), which were explored further for molecular docking studies to understand their mode of interaction with DNA. The present study opens up their possible applications as fluorescence probes for biomacromolecules like DNA in future.

Targeted release of anticancer drugs to tumor sites has a pivotal role in clinical oncology. pH-responsive drug delivery systems, with an intelligent and targeted release of anticancer drugs in a controllable manner based on sensitivities to the weakly acidic environments of tumor cellular microenvironments, are desirable. Herein, the design of such a pH-responsive drug delivery system is detailed using in situ amino-functionalized hollow mesoporous silica nanoparticles as carriers. The drug release behavior of the pH-responsive delivery system was evaluated under an in vitro simulation of tumor cellular microenvironments. The drug delivery system has efficient drug loadings and targeted release. Zorubicin hydrochloride releasing percentage is almost up to 100% at a buffer pH of 5.0. The drug release systems described demonstrating great potential in anticancer therapy.