The use of mammalian cells for therapeutic applications is finding its way into modern medicine. However, modification or "training" of cells to make them suitable for a specific application remains complex. By envisioning a chemical toolbox that enables specific, but straight-forward and generic cellular functionalization, we investigated how membrane-receptor (pre)targeting could be combined with supramolecular host-guest interactions based on β-cyclodextrin (CD) and adamantane (Ad). The feasibility of this approach was studied in cells with membranous overexpression of the chemokine receptor 4 (CXCR4). By combining specific targeting of CXCR4, using an adamantane (Ad)-functionalized Ac-TZ14011 peptide (guest; KD = 56 nM), with multivalent host molecules that entailed fluorescent β-CD-Poly(isobutylene-alt-maleic-anhydride)-polymers with different fluorescent colors and number of functionalities, host-guest cell-surface modifications could be studied in detail. A second set of Ad-functionalized entities enabled introduction of additional surface functionalities. In addition, the attraction between CD and Ad could be used to drive cell-cell interactions. Combined we have shown that supramolecular interactions, that are based on specific targeting of an overexpressed membrane-receptor, allow specific and stable, yet reversible, surface functionalization of viable cells and how this approach can be used to influence the interaction between cells and their surroundings.

Stem-cell-based tissue engineering requires increased stem cell retention, viability, and control of differentiation. The use of biocompatible scaffolds encapsulating stem cells typically addresses the first two problems. To achieve control of stem cell fate, fine-tuned biocompatible scaffolds with bioactive molecules are necessary. However, given that the fine-tuning of stem cell scaffolds is associated with UV irradiation and in situ scaffold gelation, this process is in conflict with injectability. Herein, a fine-tunable and injectable 3D hydrogel system is developed with the use of thermosensitive poly(organophosphazene) bearing β-cyclodextrin (β-CD PPZ) and two types of adamantane-peptides (Ad-peptides) that are associated with mesenchymal stem cell (MSC) differentiation and that serve as stoichiometrically controlled pendants for fine-tuning. Given that complexation of hosts and guests subject to strict stoichiometric control is achieved with simple mixing, these fabricated hydrogels exhibit well-aligned, fine-tuning responses, even in living animals. Injection of MSCs in fine-tuned hydrogels also results in various chondrogenic differentiation levels at three weeks postinjection. This is attributed to the differential controls of Ad-peptides, if MSC preconditioning is excluded. Eventually, the fine-tunable and injectable 3D hydrogel could be applied as platform technology by simply switching the types of peptides bearing adamantane and their stoichiometry.

Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl moiety. The new synthesized compounds were tested for activities against some Gram-negative and Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds 4e and 5e possessed cytotoxicity against tested human cancer cell lines.

The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than the FDA-approved arsenic trioxide. In this context, we have expanded the chemical space of polyarsenicals related to arsenicin A by synthesizing dialkyl and dimethyl thio-analogs, the latter characterized with the support of simulated NMR spectra. In addition, the new natural arsenicin D, the scarcity of which in the Echinochalina bargibanti extract had previously limited its full structural characterization, has been identified by synthesis. The dialkyl analogs, which present the adamantane-like arsenicin A cage substituted with either two methyl, ethyl, or propyl chains, were efficiently and selectively produced and evaluated for their activity on glioblastoma stem cells (GSCs), a promising therapeutic target in glioblastoma treatment. These compounds inhibited the growth of nine GSC lines more potently than arsenic trioxide, with GI50 values in the submicromolar range, both under normoxic and hypoxic conditions, and presented high selectivity toward non-tumor cell lines. The diethyl and dipropyl analogs, which present favorable physical-chemical and ADME parameters, had the most promising results.

Supramolecular and dynamic biomaterials hold promise to recapitulate the time-dependent properties and stimuli-responsiveness of the native extracellular matrix (ECM). Host-guest chemistry is one of the most widely studied supramolecular bonds, yet the binding characteristics of host-guest complexes (β-CD/adamantane) in relevant biomaterials have mostly focused on singular host-guest interactions or nondiscrete multivalent pendent polymers. The stepwise synergistic effect of multivalent host-guest interactions for the formation of dynamic biomaterials remains relatively unreported. In this work, we study how a series of multivalent adamantane (guest) cross-linkers affect the overall binding affinity and ability to form supramolecular networks with alginate-CD (Alg-CD). These binding constants of the multivalent cross-linkers were determined via NMR titrations and showed increases in binding constants occurring with multivalent constructs. The higher multivalent cross-linkers enabled hydrogel formation; furthermore, an increase in binding and gelation was observed with the inclusion of a phenyl spacer to the cross-linker. A preliminary screen shows that only cross-linking Alg-CD with an 8-arm-multivalent guest results in robust gel formation. These cytocompatible hydrogels highlight the importance of multivalent design for dynamically cross-linked hydrogels. These materials hold promise for development toward cell- and small molecule-delivery platforms and allow discrete and fine-tuning of network properties.

M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591-595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus.

A simple and highly effective methodology for the cross-coupling of heteroaryl iodides with NN-AuPPh3 at room temperature is reported. The protocol is based on a novel catalytic system consisting of Pd2(dba)3·CHCl3 and the phosphine ligand MeCgPPh having an adamantane-like framework. The present protocol was found to be well compatible with various heteroaryl iodides, thus opening new horizons in directed synthesis of functionalized nitronyl nitroxides and high-spin molecules.

Influenza virus is an acute and highly contagious respiratory pathogen that causes great concern to public health and for which there is a need for extensive drug discovery. The small chemical compound ABMA and its analog DABMA, containing an adamantane or a dimethyl-adamantane group, respectively, have been demonstrated to inhibit multiple toxins (diphtheria toxin, Clostridium difficile toxin B, Clostridium sordellii lethal toxin) and viruses (Ebola, rabies virus, HSV-2) by acting on the host's vesicle trafficking. Here, we showed that ABMA and DABMA have antiviral effects against both amantadine-sensitive influenza virus subtypes (H1N1 and H3N2), amantadine-resistant subtypes (H3N2), and influenza B virus with EC50 values ranging from 2.83 to 7.36 µM (ABMA) and 1.82 to 6.73 µM (DABMA), respectively. ABMA and DABMA inhibited the replication of influenza virus genomic RNA and protein synthesis by interfering with the entry stage of the virus. Molecular docking evaluation together with activity against amantadine-resistant influenza virus strains suggested that ABMA and DABMA were not acting as M2 ion channel blockers. Subsequently, we found that early internalized H1N1 virions were retained in accumulated late endosome compartments after ABMA treatment. Additionally, ABMA disrupted the early stages of the H1N1 life cycle or viral RNA synthesis by interfering with autophagy. ABMA and DABMA protected mice from an intranasal H1N1 challenge with an improved survival rate of 67%. The present study suggests that ABMA and DABMA are potential antiviral leads for the development of a host-directed treatment against influenza virus infection.

Oil sands process-affected waters (OSPW) contain persistent, toxic naphthenic acids (NAs), including the abundant yet little-studied diamondoid carboxylic acids. Therefore, we investigated the aerobic microbial biotransformation of two of the most abundant, chronically toxic and environmentally relevant diamondoid carboxylic acids: adamantane-1-carboxylic acid (A1CA) and 3-ethyl adamantane carboxylic acid (3EA). We inoculated into minimal salts media with diamondoid carboxylic acids as sole carbon and energy source two samples: (i) a surface water sample (designated TPW) collected from a test pit from the Mildred Lake Settling Basin and (ii) a water sample (designated 2 m) collected at a water depth of 2 m from a tailings pond. By day 33, in TPW enrichments, 71% of A1CA and 50% of 3EA was transformed, with 50% reduction in EC20 toxicity. Similar results were found for 2 m enrichments. Biotransformation of A1CA and 3EA resulted in the production of two metabolites, tentatively identified as 2-hydroxyadamantane-1-carboxylic acid and 3-ethyladamantane-2-ol respectively. Accumulation of both metabolites was less than the loss of the parent compound, indicating that they would have continued to be transformed beyond 33 days and not accumulate as dead-end metabolites. There were shifts in bacterial community composition during biotransformation, with Pseudomonas species, especially P. stutzeri, dominating enrichments irrespective of the diamondoid carboxylic acid. In conclusion, we demonstrated the microbial biotransformation of two diamondoid carboxylic acids, which has potential application for their removal and detoxification from vast OSPW that are a major environmental threat.

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood-brain barrier. According to the in vitro testing, hydroxamic acids 15 and 25, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against β-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer's disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid 15 restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer's disease.

Atomically precise engineering on the nanocluster surface remains highly desirable for the fundamental understanding of how surface structures of a nanocluster contribute to its overall properties. In this paper, the concept of "graft-onto" has been exploited to facilitate nanocluster growth on surface structures. Specifically, the Ag2(DPPM)Cl2 complex is used for re-constructing the surface structure of Pt1Ag28 (SR)18(PPh3)4 (Pt1Ag28 , SR = 1-adamantanethiolate) and producing a size-growth nanocluster - Pt1Ag31 (SR)16(DPPM)3Cl3 (Pt1Ag31 ). The grafting effect of Ag2(DPPM)Cl2 induces both direct changes on the surface structure (e.g., size growth, structural transformation, and surface rotation) and indirect changes on the kernel structure (from a fcc configuration to an icosahedral configuration). Remarkable differences have been observed by comparing optical properties between Pt1Ag28 and Pt1Ag31 . Significantly, Pt1Ag31 exhibits high photo-luminescent intensity with a quantum yield of 29.3%, which is six times that of the Pt1Ag28 . Overall, this work presents a new approach (i.e., graft-onto) for the precise dictation of nanocluster surface structures at the atomic level.

Four new compounds of the general formula [M(L)(CH3COO)][PF6], where L is a tetradentate tripodal ligand such as tris[2-(dimethylamino)ethyl]amine (L1) or (2-aminoethyl)bis(2-pyridylmethyl)amine (L2) and M is Co(II), Ni(II) or Cu(II), have been prepared employing a simple two-step synthesis. The compounds have been characterised by elemental analysis, mass spectroscopy, IR spectroscopy and X-ray diffraction. The catalytic properties of the derivatives containing the aliphatic ligand L1 have been investigated in particular toward the oxidation of cyclohexane and adamantane in the presence of the sacrificial oxidant m-CPBA (meta-chloroperbenzoic acid). Good TONs and selectivity have been determined for the cobalt and nickel compounds.

In this study, we developed poly(ɛ-caprolactone) (PCL) 3D scaffolds using a solid free form fabrication (SFF) technique. β-cyclodextrin (βCD) was grafted to hydroxyapatite (HAp) and this βCD grafted HAp was coated onto the PCL scaffold surface, followed by drug loading through an inclusion complex interaction between the βCD and adamantane (AD) or between βCD and simvastatin (SIM). The scaffold structure was characterized by scanning electron microscopy (SEM). The release profile of simvastatin in the β-CD grafted HAp was also evaluated. Osteogenic differentiation of adipose-derived stromal cells (ADSCs) was examined using an alkaline phosphatase activity (ALP) assay. The results suggest that drug loaded PCL-HAp 3-D scaffolds enhances osteogenic differentiation of ADSCs.

The layer-by-layer technique was exploited to adjust the magnitude of the host⁻guest interactions between adamantane and cyclodextrin. The effect depends on numerous complex and changeable growth profiles of the films and the number of bilayers. These composite films of mesoporous silica nanoparticles and hyaluronic acid⁻cyclodextrin(HA-CD) were constructed to load the fluorescent dyes and peptides. The release rates of these molecules would decrease with an increase in the number of layers. A laser scanning confocal microscope was utilized to obtain the diffusion coefficient of fluorescein isothiocyanate. Hybrid films could be applied to increase the loading of different kinds of molecules and could also be integrated into the lamination to delay the rate of release.

Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC50 meanings and the binding energy to the assumed biological target, the p37 viral protein with R2 = 0.60.

The valence self-regulation of sulfur from the "-2" valence state in thiols to the "-1" valence state in hydroxylated thiolates has been accomplished using the Pt1Ag28 nanocluster as a platform-the first time that the "-1" valent sulfur has been detected as S-1. Two previously unknown nanoclusters, Pt1Ag28(SR)20 and Pt1Ag28(SR)18(HO-SR)2 (where SR represents 2-adamantanethiol), have been synthesized and characterized-in the latter nanocluster, the presence of hydroxyl induces the valence regulation of two special S atoms from "-2" (in SR) to "-1" valence state in the HO-S(Ag)R. Because of the contrasting nature of the capping ligands in these two nanoclusters [i.e., only SR in Pt1Ag28(SR)20 or both SR- and HO-SR- in Pt1Ag28(SR)18(HO-SR)2], they exhibit differing shell architectures, even though their cores (Pt1Ag12) are in the same icosahedral configuration. Single-crystal x-ray diffraction analysis revealed their 1:1 cocrystallization, and mass spectrometry verified the presence of hydroxyls on Pt1Ag28(SR)18(HO-SR)2.

The recent emergence of a novel pandemic influenza A(H1N1) strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable problem as evidenced by the currently widespread oseltamivir- and adamantane-resistant seasonal influenza A viruses (IFV). Additional antiviral approaches with novel mechanisms of action are needed to combat novel and resistant influenza strains. DAS181 (Fludase) is a sialidase fusion protein in early clinical development with in vitro and in vivo preclinical activity against a variety of seasonal influenza strains and highly pathogenic avian influenza strains (A/H5N1). Here, we use in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181 against several pandemic influenza A(H1N1) viruses.

A multifunctional supramolecular assembly was successfully constructed by the host-guest complexation of doubly positively charged adamantane (ADA) with β-CD-modified hexabenzocoronene and the π-stacking of coronene with mitoxantrone, which was characterized by transmission electron microscopy, scanning electron microscopy, dynamic light-scattering, and zeta potential experiments. Possessing a small size and rigid backbone coronene center, the water-soluble biocompatible supramolecular assembly has intracellular imaging abilities. Moreover, after the ester group of ADA was hydrolyzed into a carboxyl group, the positively charged quaternary amine strand converted into a zwitterion structure, which realized the controlled plasmid DNA binding and release. Besides, the cytotoxicity experiments showed that the supramolecular assembly possesses slightly lower toxicity and a slightly higher anticancer activity than free drug. We believe that this work might present a convenient method for synergetic cancer treatment.

Drug/gene transportation systems with stimuli-responsive release behaviors are becoming research hotspots in biochemical and biomedical fields. In this work, a glucose-responsive supramolecular nanocluster was successfully constructed by the intermolecular complexation of phenylboronic acid modified β-cyclodextrin with adamantane modified polyethylenimine, which could be used as a biocompatible carrier for insulin and pCMV3-C-GFPSpark-Ins DNA which could express insulin co-delivery. Benefiting from the response capability of phenylboronic acid moiety toward glucose, the encapsulated insulin could be specifically released and the corresponding targeted DNA could efficiently express insulin in HepG2 cell, accompanied by the high-level insulin release in vitro. Our results demonstrate that the simultaneous insulin drug delivery and insulin gene transfection in a controlled mode may have great potential in the clinical diabetes treatments.

An outbreak of highly pathogenic avian influenza A (H5N1) has recently spread to poultry in 9 Asian countries. H5N1 infections have caused > or =52 human deaths in Vietnam, Thailand, and Cambodia from January 2004 to April 2005. Genomic analyses of H5N1 isolates from birds and humans showed 2 distinct clades with a nonoverlapping geographic distribution. All the viral genes were of avian influenza origin, which indicates absence of reassortment with human influenza viruses. All human H5N1 isolates tested belonged to a single clade and were resistant to the adamantane drugs but sensitive to neuraminidase inhibitors. Most H5N1 isolates from humans were antigenically homogeneous and distinct from avian viruses circulating before the end of 2003. Some 2005 isolates showed evidence of antigenic drift. An updated nonpathogenic H5N1 reference virus, lacking the polybasic cleavage site in the hemagglutinin gene, was produced by reverse genetics in anticipation of the possible need to vaccinate humans.