Versatile Dehydration-Assisted Functionalization of Quantum Dots and Rods.

Functionalization of quantum dots (QDs) and quantum rods (QRs) with ligands is essential for their further practical application across various domains. Dehydration-assisted functionalization (DAF) is a versatile method applicable to a wide range of hydrophilic ligands with an affinity to the surface of QDs and QRs. This approach facilitates rapid one-pot ligand exchange and dense modification by efficiently transferring these ligands onto the surface of QDs and QRs. This study demonstrates the efficacy of DAF in preparing chiral QRs, engineering the surface charge of QDs, utilizing QR aggregates, and conjugating dense DNA onto cadmium-free InP/ZnS QDs. DAF therefore offers a versatile solution for hydrophilic ligand functionalization of QDs and QRs applicable to diverse applications.

N-Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P- Stereogenicity.

P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96% ee, and good diastereoselectivity, with up to 14:1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.

Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity.

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ1R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Iridium-Catalyzed Domino Hydroformylation/Hydrogenation of Olefins to Alcohols: Synergy of Two Ligands.

A novel one-pot iridium-catalyzed domino hydroxymethylation of olefins, which relies on using two different ligands at the same time, is reported. DFT computation reveals different activities for the individual hydroformylation and hydrogenation steps in the presence of mono- and bidentate ligands. Whereas bidentate ligands have higher hydrogenation activity, monodentate ligands show higher hydroformylation activity. Accordingly, a catalyst system is introduced that uses dual ligands in the whole domino process. Control experiments show that the overall selectivity is kinetically controlled. Both computation and experiment explain the function of the two optimized ligands during the domino process.

Dual ligand-capped gold nanoclusters for the smart detection of specific reactive oxygen species.

Quantitative detection of different types of reactive oxygen species (ROS) is vital for understanding the crucial roles of them in biological processes. However, few researches achieved the detection of multiple types of ROS with one probe until now. Given this, we designed and prepared fluorescent gold nanoclusters capped by dual ligand bovine serum albumin and lysozyme (BSA-LYS-AuNCs), which could detect 3 specific types of ROS based on its different fluorescent responses to H2O2, •OH and ClO-, respectively. The limit of detection (LOD) of H2O2, •OH, and ClO- was as low as 0.82 µM, 0.45 µM, and 0.62 µM. Moreover, as an important ROS type, ClO- was detected with high sensitivity and low LOD by BSA-LYS-AuNCs. It was also proved that the crosslinking of protein mainly contributed to the unique fluorescent characteristics of the probe exposing to ClO-. Furthermore, the fluorescent probe achieved the smart detection of hROS (including •OH and ClO-) and wROS (the form of H2O2) in the real sample, which could also been applied specifically to the detection of antioxidants, e.g. ascorbic acid. The gold nanoclusters developed have high potential for the smart detection of multiple ROS in the body fluid of organisms.

N-Skatyltryptamines-Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential.

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

Arylboronic acids as dual-action FAAH and TRPV1 ligands.

A series of 31 arylboronic acids designed on the basis of the pharmacophore model for a variety of TRPV1 antagonists was prepared and tested on FAAH and TRPV1 channel. Four of them, that is, compounds 3c, 4a, 5a,b acted as dual FAAH/TRPV1 blockers with IC50 values between 0.56 and 8.11µM whereas ten others (compounds 1c,f-i, 2c-f, 4b) inhibited FAAH and activated/desensitized TRPV1.

High-performance CuInS2 quantum dot sensitized solar cells through I-/MPA dual-ligands passivation.

High-efficiency quantum dot sensitized solar cells (QDSSCs) can be received by increasing quantum dot (QD) loading and mitigating QD surface trap states. Herein, the surface state of CuInS2 QDs is optimized through an I-/MPA dual-ligands passivation strategy. The steric hindrance and electrostatic repulsion between QDs can be effectively reduced, thereby enabling an increased QD loading capacity. Meanwhile, the I-/MPA dual-ligands passivation strategy can further lower the surface trap density, leading to substantially enhanced charge transfer efficiency of the solar cells. Interestingly, various iodized salts, including TBAI, MAI, and KI, are proved to possess comparable property, underscoring the versatility and broad applicability of this I-/MPA dual-ligands passivation strategy. Eventually, CuInS2 QDSSCs based on the NH4I/MPA dual-ligands exhibit a noteworthy enhancement in photovoltaic conversion efficiency, surpassing the benchmark of 5.71% to reach 7.03%.

Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators.

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.

Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation.

The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ1 receptor antagonist BD-1063. The selective σ1 receptor agonist PRE-084 completely reversed this effect. Four thioamide H2S-σ1 receptor hybrids (5a-8a) and their amide derivatives (5b-8b) were synthesized. Compound 7a (AD164) robustly released H2S and showed selectivity for σ1 receptor over σ2 and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous H2S-release and σ1 antagonistic activities.

Acute myocardial infarction therapy: in vitro and in vivo evaluation of atrial natriuretic peptide and triphenylphosphonium dual ligands modified, baicalin-loaded nanoparticulate system.

BACKGROUND: Myocardial infarction (MI) is one of the most common ischemic heart diseases. It is very essential to explore new types of cardioprotective drugs delivery systems in this area. OBJECTIVE: The aim of the present study was to investigate the protective effect of baicalin (BA) and puerarin (PU) against acute MI rat models. BA and PU co-loaded nanoparticulate system were developed to improve bioavailability of the drugs, to prolong retention time in vivo and to enhance the protective effect. METHODS: In the present study, ANP and TPP contained ligands were synthesized. ANP/TPP-BN-LPNs were prepared and its physico-chemical properties were evaluated. The MI therapy efficiency of ANP/TPP-BN-LPNs was assessed in rats after intravenous injection. Single ligand contained LPNs, no ligand contained LPNs, and BN solution formulations were also prepared and used for the comparison. RESULTS: ANP/TPP-BN-LPNs were uniform and spheroidal particles. The size of ANP/TPP-BN-LPNs was 98.5 ± 2.9 nm, with a zeta potential of -19.5 ± 1.9 mV. The dual ligands modified LPNs exhibited significantly improved therapeutic efficiency compared with the single ligand modified LPNs and other systems. In vivo infarct therapy studies in rats proved that ANP/TPP-BN-LPNs were a promising system for efficient delivery of cardiovascular drugs for the treatment of cardiovascular diseases. CONCLUSIONS: ANP/TPP-BN-LPNs could be used as a long-circulating and heart-targeting drug delivery system.

Synergetic Combinations of Dual-Targeting Ligands for Enhanced In Vitro and In Vivo Tumor Targeting.

The concept of dual-ligand targeting has been around for quite some time, but remains controversial due to the intricate interplay between so many different factors such as the choice of dual ligands, their densities, ratios and length matching, etc. Herein, the synthesis of a combinatorial library of single and dual-ligand nanoparticles with systematically varied properties (ligand densities, ligand ratios, and lengths) for tumor targeting is reported. Folic acid (FA) and hyaluronic acid (HA) are used as two model targeting ligands. It is found that the length matching and ligand ratio play critical roles in achieving the synergetic effect of the dual-ligand targeting. When FA is presented on the nanoparticle surface through a 5K polyethylene glycol (PEG) chain, the dual ligand formulations using the HA with either 5K or 10K length do not show any targeting effect, but the right length of HA (7K) with a careful selection of the right ligand ratio do enhance the targeting efficiency and specificity significantly. Further in vitro 3D tumor spheroid models and in vivo xenograft mice models confirm the synergetic targeting efficiency of the optimal dual-ligand formulation (5F2H7K ). This work provides a valuable insight into the design of dual-ligand targeting nanosystems.

Transferrin and tocopheryl-polyethylene glycol-succinate dual ligands decorated, cisplatin loaded nano-sized system for the treatment of lung cancer.

Nanocarriers decorated with different ligands were used to achieve lung cancer treatment. Surface decoration of nanoparticulate system will assist in targeting the drug to specific tumor cells and tissues. The aim of this research was to develop a dual ligands decorated nanocarriers (NCs), which could increase the cell uptake and anti-tumor efficiency. Two different ligands: Transferrin (Tf) and D-α-tocopheryl polyethylene glycol succinate (TPGS) containing ligands were synthesized. Dual ligands decorated nanocarriers (DL-NCs) was constructed. The in vitro cytotoxicity, in vivo biodistribution, and in vivo antitumor efficacy of the DL-NCs were evaluated. DL-NCs can efficiently deliver cisplatin (CDDP) into lung cancer cells in vitro and reduced xenograft tumor size in vivo. The encapsulation of CDDP in the DL-NCs significantly improved the cytotoxicity and antitumor efficacy. DL-NCs held great potential for achieving an optimal therapeutic effect in the treatment of lung cancer.

Polyarginine and PEG-AEYLR comodified nanostructured lipid carrier: 10mol% uncleavable PEG-AEYLR showed no shielding effect to polyarginine in vitro while maintaining good tumor targeting in vivo.

We constructed a dual ligands-modified nanostructured lipid carrier (NLC) called PAR-NLC, in which the epidermal growth factor receptor (EGFR)-targeted small peptide AEYLR was attached to the distal end of PEG2000 anchored on the NLC surface naming PEG-AEYLR, and poly-arginine (R8) as a classic cell-penetrating peptide was attached directly to the NLC surface. PAR-NLC was near-spherical particle with average size ∼50 nm and zeta potential at +14.09 mV; the cellular uptake of PAR-NLC showed synergistic effect of the two peptides, presented as significant superior cellular uptake in EGFR-positive cells NCI-H1299 and S180 over EGFR-negative cell K562. In the animal optical imaging study, 2 h after the administration of the Dir-loaded PAR-NLC, maximum Dir signal appeared in tumor tissue, indicating prompt tumor targeting effect, as time prolonged to 48 h, the Dir signal attenuated in the organs except tumor, suggesting constant clearance from the body. In the in vivo antitumor study, in premise of the same dose, paclitaxel-loaded PAR-NLC exhibited better antitumor and safety effect than Taxol, the body weight of the mice was more stable and tumor size was smaller. In summary, PAR-NLC was a potential drug carrier to deliver anticancer drugs safely and effectively.

PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models.

Recent studies have demonstrated the utility of drugs modulating the endogenous cannabinoid system to control excessive alcohol intake. Among them, drugs interacting with acylethanolamide receptors including cannabinoid CB1 receptor antagonists/inverse agonists, peroxisome proliferator-activated receptor alpha (PPARα) agonists or peroxisome proliferator-activated receptor gamma (PPARγ) agonists have demonstrated utility in the reduction of alcohol intake in animal models. However, few studies have addressed the potential utility of combining these classes of drugs, especially because of expected safety problems. In the present work we took the advantage of the availability of two novel dual ligands for these receptors, to test the hypothesis that these types of drugs might reproduce and even improve the pharmacological profile of those drugs interacting with single targets. To this end we tested (R)-3-[(4-Benzyl-2-oxooxazolidin-3-yl)methyl]-N-[4-(dodecylcarbamoyl)phenyl]benzamide (NF 10-360), a dual PPARα/γ agonist, and N-[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA), a dual CB1 receptor antagonist/PPARα agonist, in animal models of alcohol consumption. Both drugs were effective in reducing alcohol intake and alcohol self-administration, being OLHHA a very potent alcohol intake inhibitor (EC50 0.2 mg/kg). OLHHA also reduced self-administration of the opioid oxycodone. OLHHA actions on alcohol self-administration were replicated in alcohol-preferring Marchigian-Sardinian msP rats. Repeated administration of OLHHA did result neither in tolerance nor in toxicological or deleterious metabolic changes in the liver of msP rats. These data support the feasibility of developing novel dual ligands interacting with cannabinoid targets to treat alcohol use disorder in humans.

Chemically Edited Exosomes with Dual Ligand Purified by Microfluidic Device for Active Targeted Drug Delivery to Tumor Cells.

Exosomes, which are lipid membrane-bound nanovesicles (50-150 nm in diameter), have aroused extensive attention for their potential applications in invasive molecular and stand for a new therapeutic delivery system. However, they are limited by poor targeting ability and a lack of efficient isolation techniques. Here, we present a three-dimensional nanostructured microfluidic chip, in which arrays of micropillars were functionalized with crisscrossed multiwall carbon nanotubes by chemical deposition, to capture exosomes with high efficiency through a combination of a specific recognition molecule (CD63) and the unique topography of the nanomaterials. As is proven, this nanostructured interface substantially made the immuno capturing of exosomes more efficient. A high percentage of intact vesicles <150 nm were readily purified. As a further application, we added functionality to the exosomes by a chemical editing approach for targeted drug delivery. Donor cells were labeled chemically with dual ligands (biotin and avidin) in the phospholipid membrane and encapsulated drugs in the cytosol. Though the engineered donor cells secreted exosomes, the dual ligands, together with the drugs, were inherited by the exosomes, which were then isolated with the microfluidic chip. Then, the isolated exosomes were used as drug delivery vehicles and showed strong targeting abilities to tumor cells and highly efficient receptor-mediated cellular uptake when exposed to recipient cells. Thus, the anticancer effect of chemotherapeutic drugs was improved significantly. It suggested that this platform could provide a useful tool for isolating intact exosomes with high efficiency and exploiting their natural carrier function to deliver chemotherapeutic drugs to tumor cells with increased efficacy and targeting capacity.

Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents.

A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.

Polypharmacology of dopamine receptor ligands.

Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsons disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.

Discovery of Potent Dual PPARα Agonists/CB1 Ligands.

This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpectedly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.

The cytotoxity of paclitaxel-nanoparticles with dual ligands combined with ultrasound irradiation on drug-resistant breast cancer cells / 中华超声影像学杂志

Objective To screening optimized ultrasound (US)condition for MCF-7 cells and MCF-7/Tax cells,and to investigate the effect of dual-ligands nanoparticles (NPs ) combined with US on overcoming multidrug resistance (MDR).Methods To obtain optimized US condition,cell viability and cellular uptake of NPs treated with MCF-7 cells and MCF-7/Tax cells were detected under different ultrasonic parameters including ultrasound intensity,exposure duration and microbubble concentration. MTT assay was performed to observe the effect of NPs combined with US on cells.Results The optimal US conditions for MCF-7 cells was irradiation intensity 0.6 W/cm2 ,irradiation time 80 s,and the MBs concentration with volume ratio of microbubbles to medium was 1∶1 0;and for MCF-7/Tax cells,irradiation intensity 0.6 W/cm2 ,irradiation time 80 s,and the MBs concentration with volume ratio of microbubbles to medium was 1∶20.Compared with individual NPs,NPs assisted by US exhibited greater killing ability for MCF-7 (IC50 1 .43 ng/ml)and MCF-7/Tax cells (IC50<800 ng/ml).Conclusions US effect could enhance drug sensitivity of the dual-functionized NPs for MCF-7/Tax cells,indicating that US irradiation had potential assisted modality to reverse tumor MDR.