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Two new compounds, euphorbinoside (1) and dehydropicrorhiza acid methyl diester (2), along with 24 known compounds (3-26) were isolated from Euphorbia humifusa Willd. The effects of these compounds on soluble epoxide hydrolase (sEH) inhibitory activity were evaluated. Flavonoid compounds (10-21) exhibited high sEH inhibitory activity. Among them, compounds 12, 13, and 19 greatly inhibited sEH enzymatic activity, with IC50 values as low as 18.05±1.17, 18.64±1.83, and 17.23±0.84 μM, respectively. In addition, the effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) production by RAW 264.7 cells were investigated. Compounds 3-6, 8, 18, 20-23, and 25-26 inhibited the production of both NO and TNF-α, with IC50 values ranging from 11.1±0.9 to 45.3±1.6 μM and 14.4±0.5 to 44.5±1.2 μM, respectively., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A series of novel 1,2,3-triazole-adamantylacetamide hybrids 5a-u, designed by combining bioactive fragments from antitubercular I-A09 and substituted adamantyl urea, were synthesized using copper catalyzed click chemistry. N-(1-Adamantyl)-2-azido acetamide 3 prepared from 1-adamantylamine was reacted with a series of alkyl/aryl acetylenes in the presence of copper sulfate and sodium ascorbate to give new analogues 5a-u in very good yields. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted N-(1-adamantan-1-yl)-2-(4-(phenanthren-2-yl)-1H-1,2,3-triazol-1-yl)acetamide (5t) as most promising lead MIC: 3.12 μg/mL) with selectivity index >15., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Platensimycin (PTM) and platencin (PTN) are potent inhibitors of bacterial fatty acid synthases and have emerged as promising antibacterial drug leads. We previously characterized the PTM and PTN biosynthetic machineries in the Streptomyces platensis producers. We now identify two mechanisms for PTM and PTN resistance in the S. platensis producers-the ptmP3 or ptnP3 gene within the PTM-PTN or PTN biosynthetic cluster and the fabF gene within the fatty acid synthase locus. PtmP3/PtnP3 and FabF confer PTM and PTN resistance by target replacement and target modification, respectively. PtmP3/PtnP3 also represents an unprecedented mechanism for fatty acid biosynthesis in which FabH and FabF are functionally replaced by a single condensing enzyme. These findings challenge the current paradigm for fatty acid biosynthesis and should be considered in future development of effective therapeutics targeting fatty acid synthase., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neuropathic pain is a serious physical disabling condition resulting from lesion or dysfunction of the peripheral sensory nervous system. Despite the fact that the mechanisms underlying neuropathic pain are poorly understood, the involvement of voltage-gated calcium (Ca(V)) channels in its pathophysiology has justified the use of drugs that bind the Ca(V) channel α₂δ auxiliary subunit, such as gabapentin (GBP), to attain analgesic and anti-allodynic effects in models involving neuronal sensitization and nerve injury. GBP binding to α₂δ inhibits nerve injury-induced trafficking of the α₁ pore forming subunits of Ca(V) channels, particularly of the N-type, from the cytoplasm to the plasma membrane of pre-synaptic terminals in dorsal root ganglion neurons and dorsal horn spinal neurons. In the search for alternative forms of treatment, in this study we describe the synthesis and pharmacological profile of a GABA derivative, 2-aminoadamantane-1-carboxylic acid (GZ4), which displays a close structure-activity relationship with GBP. Behavioral assessment using von Frey filament stimuli showed that GZ4 treatment reverted mechanical allodynia/hyperalgesia in an animal model of spinal nerve ligation-induced neuropathic pain. In addition, using the patch clamp technique we show that GZ4 treatment significantly decreased whole-cell currents through N-type Ca(V) channels heterologously expressed in HEK-293 cells. Interestingly, the behavioral and electrophysiological time course of GZ4 actions reflects that its mechanism of action is similar but not identical to that of GBP. While GBP actions require at least 24 h and imply uptake of the drug, which suggests that the drug acts mainly intracellularly affecting channels trafficking to the plasma membrane, the faster time course (1-3 h) of GZ4 effects suggests also a direct inhibition of Ca(2+) currents acting on cell surface channels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A novel guest biomimetic glutathione peroxidase (3,3'-tellurobis(propane-3,1-diyl) diadamantanecarboxylate, denoted as ADA-Te-ADA) was synthesized. ADA-Te-ADA functioned to overcome the disadvantages in the construction of building block for giant supramolecular biomimetic enzyme. To reveal the catalytic property of hydrophobic ADA-Te-ADA, the catalytic mechanism was investigated using PBS (phosphate buffer (pH 7.0. 50 mM))/methanol solvent mixture as assay solution. Itindicated that ADA-Te-ADA exhibited typical enzyme catalytic behavior by saturation kinetics measurement. Importantly, ADA-Te-ADA exhibited the typical solvent-dependent catalytic behavior. And the highest catalytic rate 4.29 µM x min-1 was obtained when the volume ratio of PBs: methanol was 5 : 5. Especially, the catalytic rates obtained based on various substrates proved that ADA-Te-ADA slightly displayed special substrate selectivity, which was the ideal catalytic characterization of building block for giant supramolecular biomimetic enzyme. The successfully synthesis of ADA-Te-ADA might highlight for the understanding of the catalytic mechanism of hydrophobic guest biomimetic glutathione peroxidase. And it also might provide the basement for the construction of giant supramolecular biomimetic enzyme.

(14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of (14)C-labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [(14)C]CH2 I2 starting material. By following similar synthetic routes, 580.0 mg of (13)CD2-labeled saxagliptin and 153.1 mg of (13)CD2-labeled 5-hydroxysaxagliptin metabolite were prepared., (Copyright © 2014 John Wiley & Sons, Ltd.)

A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Synthesis of 3-deoxy-3a-homo-3a-aza-derivatives of betulin and erythrodiol from betulonic and oleanonic acids was carried out. The most antineoplastic activity with a wide range of action at in vitro testing showed 3-deoxy-3a-homo-3a-aza-28-hydroxy-12(13)-oleanene, which by results of profound studying could be recommended for in vivo investigation. Its modification in the C28 position by introduction of amethoxycinnamoyl fragment led to a loss of antineoplastic activity. 3-Deoxy-3a-homo-3a-aza-derivatives of betulin (3-(aminopropyl)-, 28-(2-carboxyethyl)carboxy-, and 28-cinnamoyloxy-) showed moderate antineoplastic activity in the case of Colon Cancer, Breast Cancer and Leukemia cell lines.

All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We recently reported on a series of retinoid-related molecules containing an adamantyl group, a.k.a. adamantyl arotinoids (AdArs), that showed significant cancer cell growth inhibitory activity and activated RXRα (NR2B1) in transient transfection assays while devoid of RAR transactivation capacity. We have now explored whether these AdArs could also bind and inhibit IKKβ, a known target that mediates the induction of apoptosis and cancer cell growth inhibition by related AdArs containing a chalcone functional group. In addition, we have prepared and evaluated novel AdArs that incorporate a central heterocyclic ring connecting the adamantyl-phenol and the carboxylic acid at the polar termini. Our results indicate that the majority of the RXRα activating compounds lacked IKKβ inhibitory activity. In contrast, the novel heterocyclic AdArs containing a thiazole or pyrazine ring linked to a benzoic acid motif were potent inhibitors of both IKKα and IKKβ, which in most cases paralleled significant growth inhibitory and apoptosis inducing activities., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A data set of 1-adamantylthiopyridine analogs (1-19) with antioxidant activity, comprising of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dismutase (SOD) activities, was used for constructing quantitative structure-activity relationship (QSAR) models. Molecular structures were geometrically optimized at B3LYP/6-31g(d) level and subjected for further molecular descriptor calculation using Dragon software. Multiple linear regression (MLR) was employed for the development of QSAR models using 3 significant descriptors (i.e. Mor29e, F04[N-N] and GATS5v) for predicting the DPPH activity and 2 essential descriptors (i.e. EEig06r and Mor06v) for predicting the SOD activity. Such molecular descriptors accounted for the effects and positions of substituent groups (R) on the 1-adamantylthiopyridine ring. The results showed that high atomic electronegativity of polar substituent group (R = CO2H) afforded high DPPH activity, while substituent with high atomic van der Waals volumes such as R = Br gave high SOD activity. Leave-one-out cross-validation (LOO-CV) and external test set were used for model validation. Correlation coefficient (QCV) and root mean squared error (RMSECV) of the LOO-CV set for predicting DPPH activity were 0.5784 and 8.3440, respectively, while QExt and RMSEExt of external test set corresponded to 0.7353 and 4.2721, respectively. Furthermore, QCV and RMSECV values of the LOO-CV set for predicting SOD activity were 0.7549 and 5.6380, respectively. The QSAR model's equation was then used in predicting the SOD activity of tested compounds and these were subsequently verified experimentally. It was observed that the experimental activity was more potent than the predicted activity. Structure-activity relationships of significant descriptors governing antioxidant activity are also discussed. The QSAR models investigated herein are anticipated to be useful in the rational design and development of novel compounds with antioxidant activity., (Crown Copyright © 2013. Published by Elsevier Masson SAS. All rights reserved.)

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A dimeric GdAAZTA-like complex (AAZTA is 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) bearing an adamantyl group (Gd2L1) able to form strong supramolecular adducts with specific hosts such as β-cyclodextrin (β-CD), poly-β-CD, and human serum albumin (HSA) is reported. The relaxometric properties of Gd2L1 were investigated in aqueous solution by measuring the (1)H relaxivity as a function of pH, temperature, and magnetic field strength. The relaxivity of Gd2L1 (per Gd atom) at 40 MHz and 298 K is 17.6 mM(-1) s(-1), a value that remains almost constant at higher fields owing to the great compactness and rigidity of the bimetallic chelate, resulting in an ideal value for the rotational correlation time for high-field MRI applications (1.5-3.0 T). The noncovalent interaction of Gd2L1 with β-CD, poly-β-CD, and HSA and the relaxometric properties of the resulting host-guest adducts were investigated using (1)H relaxometric methods. Relaxivity enhancements of 29 and 108 % were found for Gd2L1-β-CD and Gd2L1-poly-β-CD, respectively. Binding of Gd2L1 to HSA (KA = 1.2 × 10(4) M(-1)) results in a remarkable relaxivity of 41.4 mM(-1) s(-1) for the bound form (+248 %). The relaxivity is only limited by the local rotation of the complex within the binding site, which decreases on passing from Gd2L1-β-CD to Gd2L1-HSA. Finally, the applicability of Gd2L1 as tumor-targeting agent through passive accumulation of the HSA-bound adduct was evaluated via acquisition of magnetic resonance images at 1 T of B16-tumor-bearing mice. These experiments indicate a considerable signal enhancement (+160 %) in tumor after 60 min from the injection and a very low hepatic accumulation.

The characterization of absolute bioavailability (BA) is useful for non-intravenous (iv.) formulations during drug development and is required by some health authorities. A study design of co-administrating an iv. isotopically labeled microdose with a therapeutic oral dose is a viable approach for the determination of human PK and has been accepted by regulatory agencies. The implementation of an iv.-microdose with oral therapeutic dose in absolute BA studies speeds up clinical development. In recent years, AMS to measure a radiolabeled microdose has been utilized to support several clinical absolute BA studies. An alternative approach for conducting microdose studies is using LC-MS/MS alone to quantitate both the iv. drug and the oral drug. Because both labeled and unlabeled drugs can be measured simultaneously with LC-MS/MS, it is cost effective. However, for compounds with high volume of distribution and/or poor LC-MS/MS response, AMS still provides a superior LLOQ. In this Perspective, we discuss a paradigm for selecting either an LC-MS/MS or AMS-based approach for generating concentration data in absolute BA studies dependent on the required sensitivity.

An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.

Dendrons used as synthetic carriers are promising nanostructures for biomedical applications. Some polycationic dendritic systems, such as the commercially available polyethylenimine (PEI), have the ability to deliver genetic material into cells. Nevertheless, polycationic vectors are often associated with potential cellular toxicity, which prevents their use in clinical development. In this context, our research focused on the design and synthesis of a novel type of polycationic dendrons that are able to penetrate into cells without triggering cytotoxic effects. We synthesized first- and second-generation polycationic adamantane-based dendrons via a combined protection/deprotection strategy starting from different adamantane scaffolds. The linker between the adamantane cores is constituted of short ethylene glycol chains, and the periphery consists of ammonium and guanidinium groups. None of these dendritic structures, which we previously called HYDRAmers, displayed significant cytotoxicity effects on two different cell lines (RAW 264.7 and HeLa). Conjugation of the fluorescent probe cyanine 5 at their focal point via click chemistry permitted the evaluation of their cellular internalization. All of the dendrons penetrated through the membrane with efficient cellular uptake depending of the dendron generation and the nature of the peripheral groups. These results suggest that the polycationic HYDRAmers are potentially interesting as new vectors in biomedical applications, including gene and drug delivery.

Soluble epoxide hydrolase (sEH) is a promising new target for treating hypertension and inflammation. Considerable efforts have been devoted to develop novel inhibitors. In this study, the binding modes and interaction mechanisms of a series of adamantyl-based 1,3-disubstituted urea inhibitors were investigated by molecular docking, molecular dynamics simulations, binding free energy calculations, and binding energy decomposition analysis. Based on binding affinity, the most favorable binding mode was determined for each inhibitor. The calculation results indicate that the total binding free energy (ΔGTOT, the sum of enthalpy ΔGMM-GB/SA, and entropy -TΔS) presents a good correlation with the experimental inhibitory activity (IC50, r(2) = .99). The van der Waals energy contributes most to the total binding free energy (ΔGTOT). A detailed discussion on the interactions between inhibitors and those residues located in the active pocket is made based on hydrogen bond and binding modes analysis. According to binding energy decomposition, the residues Asp333 and Trp334 contribute the most to binding free energy in all systems. Furthermore, Hip523 plays a major role in determining this class of inhibitor-binding orientations. Combined with the results of hydrogen bond analysis and binding free energy, we believe that the conserved hydrogen bonds play a role only in anchoring the inhibitors to the exact site for binding and the number of hydrogen bonds may not directly relate to the binding free energy. The results we obtained will provide valuable information for the design of high potency sEH inhibitors.

Tuberculosis is a major global health problem. In the middle of the last century several laboratories identified, developed and synthesized several substances which were active against Mycobacterium tuberculosis, the causative agent of the disease. In the 1980s the standard oral treatment regimen was introduced with isoniazid, rifampicin, pyrazinamide, and ethambutol. In combination with the DOTS strategy it was possible treat TB within 6-8 months. But with the emergence of drug resistant strains, the formerly successful regiment became ineffective for MDR and XDR TB patients. Even more alarming, the rapidly increasing HIV epidemic also increases the number of HIV-related TB. Facing these facts, it became evident that novel strategies and antibiotics were needed to treat the new forms of TB. But over the last 60 years no novel TB drug was developed or even in the drug pipeline. But during the last ten years several novel substances have been developed to combat the deadly disease. For the first time in decades the TB drug pipeline is filled again with several promising compounds and many of them have reached Phase II and Phase III clinical trials. Several laboratories and companies all over the world currently are developing and evaluating these substances. This review presents novel substances, which were for the first time exclusively developed for TB such as bedaquilines, nitroimidazoles and the diamine SQ109. We also summarize the present knowledge about enzymes and biosynthesis pathways which offer potential targets for drug discovery against M. tuberculosis.

AP736 was identified as an antimelanogenic drug that can be used for the prevention of melasma, freckles, and dark spots in skin by acting as a suppressor of melanin synthesis and tyrosinase expression. Since macrophage-mediated inflammatory responses are critical for skin health, here we investigated the potential anti-inflammatory activity of AP736. The effects of AP736 on various inflammatory events such as nitric oxide (NO)/prostaglandin (PG) E2 production, inflammatory gene expression, phagocytic uptake, and morphological changes were examined in RAW264.7 cells. AP736 was found to strongly inhibit the production of both NO and PGE2 in lipopolysaccharide- (LPS-) treated RAW264.7 cells. In addition, AP736 strongly inhibited both LPS-induced morphological changes and FITC-dextran-induced phagocytic uptake. Furthermore, AP736 also downregulated the expression of multiple inflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase- (COX-) 2, and interleukin- (IL-) 1β in LPS-treated RAW264.7 cells. Transcription factor analysis, including upstream signalling events, revealed that both NF-κB and AP-1 were targeted by AP736 via inhibition of the IKK/IκBα and IRAK1/TAK1 pathways. Therefore, our results strongly suggest that AP736 is a potential anti-inflammatory drug due to its suppression of NF-κB-IKK/IκBα and AP-1-IRAK1/TAK1 signalling, which may make AP736 useful for the treatment of macrophage-mediated skin inflammation.

Four series of 1,3-diaza-2-functionalized-adamantan-6-one derivatives, bearing at the 2 position SO, SO₂, POCl and PO₂H functional groups, were synthesized via a key quadruple Mannich reaction, followed by transformation of an aminal functionality into the final 2-thia- and 2-phospha compounds. The compounds were tested for cytotoxic activity against the mouse B16-F10 melanoma cell line. Malignant melanoma is notorious for its high resistance to chemotherapy, and new anti-melanoma drugs are urgently needed. The 2-thia compounds exhibited poor proliferation inhibition activity, but the 2-phospha derivatives showed significant activity, with IC₅₀ values of 10-60 µM. The compounds induced cell death by G₂/M cell cycle arrest, which led to apoptosis, as determined by Annexin V-FITC/PI staining, mitochondrial membrane potential changes assessed by the JC-1 reagent, caspases 3 and 7 activation, and morphological changes.

Biomimetic deep-cavity cavitand hosts possess unique recognition and encapsulation properties that make them capable of selectively binding a range of non-polar guests within their hydrophobic pocket. Adamantane based derivatives which snuggly fit within the pocket of octa-acid deep cavity cavitands exhibit some of the strongest host binding. Here we explore the roles of guest size and attractiveness on optimizing guest binding to form 1:1 complexes with octa-acid cavitands in water. Specifically we simulate the water-mediated interactions of the cavitand with adamantane and a range of simple Lennard-Jones guests of varying diameter and attractive well-depth. Initial simulations performed with methane indicate hydrated methanes preferentially reside within the host pocket, although these guests frequently trade places with water and other methanes in bulk solution. The interaction strength of hydrophobic guests increases with increasing size from sizes slightly smaller than methane to Lennard-Jones guests comparable in size to adamantane. Over this guest size range the preferential guest binding location migrates from the bottom of the host pocket upwards. For guests larger than adamantane, however, binding becomes less favorable as the minimum in the potential-of-mean force shifts to the cavitand face around the portal. For a fixed guest diameter, the Lennard-Jones well-depth is found to systematically shift the guest-host potential-of-mean force to lower free energies, however, the optimal guest size is found to be insensitive to increasing well-depth. Ultimately our simulations show that adamantane lies within the optimal range of guest sizes with significant attractive interactions to match the most tightly bound Lennard-Jones guests studied.

We have developed a kind of gold nanoparticle (AuNP) in which polyethylene glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAM) are attached on the surface of a gold nanocrystal through the host-guest inclusion between adamantane groups (ADA) and β-cyclodextrin (β-CD). The resulting AuNPs become amphiphilic in water above body temperature and self-assemble into vesicles. It is found that these vesicles can load doxorubicin (Dox) effectively. With a decrease in temperature, the PNIPAM shifted from hydrophobic to hydrophilic, causing Au vesicles to disassemble into stable small AuNPs, triggering the release of Dox. These hybrid vesicles, combining polymer functionality with the intriguing properties of AuNPs, can first release free Dox and AuNP/Dox at a site of a tumor through the application of either simple ice packs or deeply penetrating cryoprobes, then the AuNP/Dox can be taken in by tumor cells and destroy them like miniature munitions. Furthermore, these vesicles showed other therapeutic possibilities due to the presence of gold. We believe that the development of such multi-functional vesicles will provide new and therapeutically useful means for medical applications.

Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells.

Despite several advantages of covalent inhibitors (such as increased biochemical efficiency, longer duration of action on the target, and lower efficacious doses) over their reversible binding counterparts, there is a reluctance to use covalent inhibitors as a drug design strategy in pharmaceutical research. This reluctance is due to their anticipated reactions with nontargeted macromolecules. We hypothesized that there may be a threshold limit for nonspecific covalent binding, below which a covalent binding drug may be less likely to cause toxicity due to irreversible binding to off-target macromolecules. Estimation of in vivo covalent binding burden from in vitro data has previously been used as an approach to distinguish those agents more likely to cause toxicity (e.g., hepatotoxicity) via metabolic activation to reactive metabolites. We have extended this approach to nine covalent binding drugs to determine in vitro covalent binding burden. In vitro covalent binding burden was determined by incubating radiolabeled drugs with pooled human hepatocytes. These data were scaled to an estimate of in vivo covalent binding burden by combining the in vitro data with daily dose. Scaled in vivo daily covalent binding burden of marketed covalent drugs was found to be under 10 mg/day, which is in agreement with previously reported threshold value for metabolically activated reversible drugs. Covalent binding was also compared to the intrinsic reactivities of the covalent inhibitors assessed using nucleophiles glutathione and N-α-acetyl lysine. The intrinsic reactivity did not correlate with observed in vitro covalent binding, which demonstrated that the intrinsic reactivity of the electrophilic groups of covalent drugs does not exclusively account for the extent of covalent binding. The ramifications of these findings for consideration of using a covalent strategy in drug design are discussed.

Fasciolosis is a parasitosis caused by the food-borne trematode Fasciola spp. of major veterinary significance. Triclabendazole is the first line treatment in humans and animals but cases of resistance are spreading worldwide. The synthetic peroxides OZ78 and MT04 are lead compounds for the treatment of fasciolosis. In the present study we investigated the efficacy and drug disposition following a single intramuscular dose of 100 mg/kg OZ78 and MT04 in sheep harbouring a natural Fasciola hepatica infection. A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify plasma and bile concentrations of both compounds. Plasma samples were analysed with an accuracy for OZ78 and MT04 from 91 to 115% and a precision lower than 8.9%. Bile samples displayed an accuracy between 92 and 101% and a precision up to 12.7%. Bile samples were collected at 0 and 6h post-administration. Plasma mean peak concentration was 11.1 μg/ml at 1.5 h for OZ78 and 4.8 μg/ml at 4.2 h for MT04. Mean AUC of OZ78 and MT04 was 6698 and 3567 μg min/ml, respectively. Bile concentration at 6h post-treatment was 1.0 μg/ml for OZ78 and 1.4 μg/ml for MT04. Treatment with OZ78 showed no effect on egg burden and adult worm counts in vivo, whereas MT04 displayed a significant egg count reduction of 98.5% and a worm burden reduction of 92%. In conclusion, our study reveals an excellent activity of MT04 against F. hepatica in naturally infected sheep and a first insight into its PK behaviour., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Shear-thinning hydrogels afford direct injection or catheter delivery to tissues without potential premature gel formation and delivery failure or the use of triggers such as chemical initiators or heat. However, many shear-thinning hydrogels require long reassembly times or exhibit rapid erosion. We developed a shear-thinning hyaluronic acid (HA) hydrogel based on the guest-host interactions of adamantane modified HA (guest macromer, Ad-HA) and β-cyclodextrin modified HA (host macromer, CD-HA). The ability of the guest and host molecules to interact with their counterpart following conjugation to HA was confirmed by (1)H NMR spectroscopy and was similar to that of the native complex. Mixing of Ad-HA and CD-HA resulted in rapid formation of a hydrogel composed of guest-host bonds. The hydrogel physical properties, including mechanics and flow characteristics, were dependent on cross-link density and network structure, which were controlled through macromer concentration, the extent of guest macromer modification, and the molar ratio of guest and host functional groups. The guest-host assembly mechanism permitted both shear-thinning behavior for ease of injection and near-instantaneous reassembly for material retention at the target sight. The hydrogel erosion and release of a model biomolecule were also dependent on design parameters and were sustained for over 60 days. These hydrogels show potential as a minimally invasive injectable hydrogel for biomedical applications.

Chiral polycyclic aromatic hydrocarbons containing bis(1-adamantyl) groups at the peri-positions, named equatorenes, were synthesized in optically pure form starting from optically pure 4,5-bis(1-adamantyl)-8-methoxy-1-naphthol. A sequential Diels-Alder reaction of furan and arynes generated from 1,2-bromotriflates provided tricyclic and tetracyclic epoxides, and acid-catalyzed aromatization gave phenanthrol and chrysenol. Deoxygenation reactions involving the hydrogenolysis of triflates gave 1,8-bis(1-adamantyl)naphthalene, 1,10-bis(1-adamantyl)phenanthrene, and 1,12-bis(1-adamantyl)chrysene. 3,4-Bis(1-adamantyl)pyrene was synthesized from phenanthrol by Sonogashira coupling and Pt-catalyzed cyclization. Essentially no racemization occurred during the synthesis. X-ray analysis indicated the distorted naphthalene moiety possessing the peri-diadamantyl groups and the flat structure of the other benzene rings. UV-vis analysis of the equatorenes showed considerable redshifts compared with that of the corresponding achiral arenes. Electrochemical analysis of the naphthalene and pyrene indicated that the distortion decreased the highest occupied molecular orbital stability with no marked effect on the lowest unoccupied molecular orbital energy level, and the origin was discussed on the basis of calculation results.

Melanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. The expression of microphthalmia-associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element-binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP-PKA-CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP-PKA-CREB-mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An improved methodology for the preparation of enantiopure oxabicyclo[3.2.1]octadienes via a stereodivergent resolution is reported. High catalyst control proximal to the oxabridged stereocenter produces readily separable diastereomers in high yield (>92%) and with excellent optical purity (>95% ee). This resolution strategy is amenable to large-scale preparations, and the utility of the resolution was further demonstrated in the asymmetric preparation of a key intermediate used in the synthesis of the antibiotic (-)-platensimycin.

The reaction of 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thione 5a,b and 10a,b with formaldehyde solution and various primary aromatic amines or 1-substituted piperazines yielded the corresponding N-Mannich bases 6a-o, 7a-g and 11a-i. The newly synthesized N-Mannich bases 6a-o, 7a-g and 11a-i were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. The compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f, 11h and 11i displayed moderate to good activity against the tested Gram-positive bacteria, while compounds 7c, 11c, 11d, 11f and 11h showed potent broad spectrum antibacterial activity. None of the newly synthesized compounds were proved to possess marked activity against C. albicans., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The surface-active properties of 1-boraadamantane have been studied using model phospholipid monolayers. Results suggest that the increase in 1-boraadamantane concentrations from 10(-7) to 10(-6) M is accompanied by the increase of the area per phospholipid molecule. This decreases to frequency of lateral diffusion of phospholipids molecules, the potential difference and the angle of the phospholipid monolayer arrangement. These phenomena may lead to impossibility of interaction between the virus and cell membranes.

Molecular dynamics characterisations in solids can be carried out selectively using dipolar-dephasing experiments. Here we show that the introduction of a sum of Lorentzian and Gaussian functions greatly improve fittings of the "intensity versus time" data for protonated carbons in dipolar-dephasing experiments. The Lorentzian term accounts for remote intra- and intermolecular (1)H-(13)C dipole-dipole interactions, which vary from one molecule to another or for different carbons within the same molecule. Thus, by separating contributions from weak remote interactions, more accurate Gaussian decay constants, T(dd), can be extracted for directly bonded (1)H-(13)C dipole-dipole interactions. Reorientations of the (1)H-(13)C bonds lead to the increase of T(dd), and by measuring dipolar-dephasing constants, insight can be gained into dynamics in solids. We have demonstrated advantages of the method using comparative dynamics studies in the α and γ polymorphs of glycine, cyclic amino acids L-proline, DL-proline and trans-4-hydroxy-L-proline, the Ala residue in different dipeptides, as well as adamantane and hexamethylenetetramine. It was possible to distinguish subtle differences in dynamics of different carbon sites within a molecule in polymorphs and in L- and DL-forms. The presence of overall molecular motions is shown to lead to particularly large differences in dipolar-dephasing experiments. The differences in dynamics can be attributed to differences in noncovalent interactions. In the case of hexamethylenetetramine, for example, the presence of C-H···N interactions leads to nearly rigid molecules. Overall, the method allows one to gain insight into the role of noncovalent interactions in solids and their influence on the molecular dynamics.

Highly cytotoxic C7-modified colchicine analogues, exemplified by tubuloclustin, promote microtubule disassembly followed by the formation of very stable tubulin clusters, both in vitro and in cells. The proposed mechanism of action of tubuloclustin and its analogues, beyond that of colchicine, includes additional specific interactions with the α-tubulin subunit., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A mild and efficient dual-mode Lewis acid induced Diels-Alder (DA)/carbocyclization cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr2 as the dual-mode Lewis acid, a series of substituted enones and dienes underwent DA/carbocyclization cascade cyclization reaction smoothly at room temperature and provided the tricyclic cyclized products in one pot with good yields and high diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin.

We propose linear end-to-end assemblies of short DNA duplexes based on β-cyclodextrin-adamantane complexation. The assembled duplexes exhibited increased Tm values compared with those of the corresponding natural hybrids. Competition experiments with external guest molecules showed a substantial decrease in Tm of the terminal modified duplexes, suggesting the viability of inter-duplex complexation.

The self-assembly of cyclodextrin (CD) functionalized graphene (GR) and adamantane-modified horseradish peroxidase (HRP-ADA) by host-guest supramolecular interaction into novel nanostructures in aqueous solution is reported in the present study. Electrochemical impedance spectroscopy and cyclic voltammetry were applied to characterize the self-assembly process and study the electrochemical behaviors of the immobilized proteins. UV-vis spectra indicated that the native structure of HRP was maintained after the assembly, implying good biocompatibility of CD-functionalized GR (CD-GR). Furthermore, the HRP-ADA/CD-GR composites were utilized for the fabrication of enzyme electrodes (HRP-ADA/CD-GR electrodes). The proposed biosensor showed good reproducibility and high sensitivity to H2O2 with the detection limit of 0.1 μM. In the range of 0.7-35 μM, the catalytic reduction current of H2O2 was proportional to H2O2 concentration., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Parkinson disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra region of the brain. Iron content is also elevated in this region in PD and is implicated in the pathobiology of the disease. Desferrioxamine B (DFOB) is a high-affinity iron chelator and has shown efficacy in animal models of Parkinson disease. The high water solubility of DFOB, however, attenuates its ability to enter the brain. In this study, we have conjugated DFOB to derivatives of adamantane or the clinical iron chelator deferasirox to produce lipophilic compounds designed to increase the bioavailability of DFOB to brain cells. We found that the novel compounds are highly effective in preventing iron-mediated paraquat and hydrogen peroxide toxicity in neuronal-like BE2-M17 dopaminergic cells, primary neurons, and iron-loaded or glutathione-depleted primary astrocytes. The compounds also alleviated paraquat toxicity in BE2-M17 cells that express the PD-causing A30P mutation of α-synuclein. This protection was ∼66-fold more potent than DFOB alone and also more effective than other cell-permeative metal chelators, clioquinol and phenanthroline. These results demonstrate that increasing the bioavailability of DFOB through the conjugation of lipophilic fragments greatly enhances its protective capacity. These novel compounds have potential as therapeutics for the treatment of PD and other conditions of Fe dyshomeostasis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.

A series of PTA and DAPTA platinum(II) and palladium(II) thionate complexes of the type trans-[M(SN)2P2] were prepared from the reaction of cis-[MCl2P2] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)] with the in situ generated sodium salts of the heterocyclic thiones S-m-methylpyrimidine-2-thione, S-4,6-dimethylpyrimidine-2-thione, S-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, S-1,3,4,-thiadiazole-2-thione, S-4,5-H-thiazolan-2-thione, and S-pyrimidine-4(1H)-one-2-thione. The X-ray structures of six of the compounds confirm the trans disposition and, only in the case of [Pd2Cl2(S-pyrimidine-4(1H)-one-2-thionate)2(PTA)2], a dinuclear structure with a Pd-Pd distance of 3.0265(14)Å was observed. In vitro cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC50) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines.

Supramolecular hydrogels formed by a host-guest interaction show self-healing properties. The cube-shaped hydrogels with β-cyclodextrin and adamantane guest molecules mend after being broken. The hydrogels sufficiently heal to form a single gel, and the initial strength is restored. Although contact between a freshly cut and uncut surface does not mend the gels, two freshly cut surfaces selectively mend., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The new series of silver(I) coordination polymers [Ag(N-N)(μ-PTA)]n(X)n (1, 2, 4-8, 10, 11) and discrete monomers [Ag(N-N)(PTA)2](X) (3, 9) {N-N = bpy (1-3), dtbpy (4), neocup (5, 6), phen (7-9), dione (10, 11); X = NO3 (1, 3, 5, 7, 9, 10), PF6 (2, 4, 6, 8, 11)} were generated by self-assembly reactions, in MeOH at ~25 °C, of AgNO3 or AgPF6 with 1,3,5-triaza-7-phosphaadamantane (PTA) and the corresponding polypyridines, namely 2,2'-bipyridine (bpy), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy), 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neocup) and 1,10-phenanthroline-5,6-dione (dione). The compounds were obtained as air and light stable solids and characterized by IR, (1)H and (31)P{(1)H} NMR spectroscopy, ESI(+)-MS and elemental analyses. The crystal structure of 1 was determined by single crystal X-ray diffraction analysis, revealing infinite one-dimensional (1D) linear chains driven by μ-PTA N,P-linkers. Apart from representing the first examples of the metal-PTA derivatives bearing polypyridine ligands, 1-11 also feature solubility in water (S(25°C) ≈ 4-18 mg mL(-1)). Selected compounds (1, 3, 5, 7, 9 and 10) were thus tested for their biological properties and found to exhibit significant antibacterial and antifungal activities, screened in vitro against the standard strains of Staphylococcus aureus, Staphylococcus pyogenes, Staphylococcus pneumoniae, Staphylococcus sanguinis, Staphylococcus mutans, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and Candida albicans. Furthermore, the compounds 5, 7, 9 and 10 show a pronounced antiproliferative activity against human malignant melanoma (A375), and the effects on the inhibition of tumor cells in vitro are in agreement with the DNA-binding studies.

In recent years, various dipeptidyl peptidase IV (DPP-4) inhibitors have been released as therapeutic drugs for type 2 diabetes in many countries. In spite of their diverse chemical structures, no comparative studies of their binding modes in the active site of DPP-4 have been disclosed. We determined the co-crystal structure of vildagliptin with DPP-4 by X-ray crystallography and compared the binding modes of six launched inhibitors in DPP-4. The inhibitors were categorized into three classes on the basis of their binding subsites: (i) vildagliptin and saxagliptin (Class 1) form interactions with the core S1 and S2 subsites and a covalent bond with Ser630 in the catalytic triad; (ii) alogliptin and linagliptin (Class 2) form interactions with the S1' and/or S2' subsites in addition to the S1 and S2 subsites; and (iii) sitagliptin and teneligliptin (Class 3) form interactions with the S1, S2 and S2 extensive subsites. The present study revealed that the additional interactions with the S1', S2' or S2 extensive subsite may increase DPP-4 inhibition beyond the level afforded by the fundamental interactions with the S1 and S2 subsites and are more effective than forming a covalent bond with Ser630., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A series of N-acyl derivatives of 5-fluorouracil (5-FU) bearing residues of palmitic, p-myristoylaminobenzoic, p-oleoylaminobenzoic, and 1-adamantanecarbonic acids was synthesized. Relative rates of hydrolysis of derivatives mentioned under physiological conditions, at pH 7.2 and 37 degrees C, have shown that stability of these compounds increases with reducing of spatial accessibility of amide group at N1 in 5-FU. These substances incorporate easily into lipid bilayer; their liposomal preparations showed substantial cytostatic activity on HBL (human breast lymphoma) cells and are of interest as potential antitumor preparations. Also, a fluorescent analog, 1-[8-(3-perylenyl)octanoyl]-5-fluorouracil, destined for studies of the 5-FU derivatives behavior in cells and tissues was prepared.

Herein, we report the development of highly potent HDAC inhibitors for the treatment of cancer. A series of adamantane and nor-adamantane based HDAC inhibitors were designed, synthesized and screened for the inhibitory activity of HDAC. A number of compounds exhibited GI50 of 10-100 nM in human HCT116, NCI-H460 and U251 cancer cells, in vitro. Compound 32 displays efficacy in human tumour animal xenograft model., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A new synthesis procedure for highly crosslinked macroporous amphiphilic N-adamantyl-functionalized mixed-mode acrylamide-based monolithic stationary phases for capillary electrochromatography (CEC) is investigated employing solubilization of the hydrophobic monomer by complexation with a cyclodextrin. N-(1-adamantyl)acrylamide is synthesized and characterized as a hydrophobic monomer forming a water soluble-inclusion complex with statistically methylated-β-cyclodextrin. The stoichiometry, the complex formation constant and the spatial arrangement of the formed complex are determined. Mixed-mode monolithic stationary phases are synthesized by in situ free radical copolymerization of cyclodextrin-solubilized N-adamantyl acrylamide, a water soluble crosslinker (piperazinediacrylamide), a hydrophilic monomer (methacrylamide), and a negatively charged monomer (vinylsulfonic acid) in aqueous medium in bind silane-pretreated fused silica capillaries. The synthesized monolithic stationary phases are amphiphilic and can be employed in the reversed- and in the normal-phase mode (depending on the composition of the mobile phase), which is demonstrated with polar and non-polar analytes. Observations made with polar analytes and polar mobile phase can only be explained by a mixed-mode retention mechanism. The influence of the total monomer concentration (%T) on the chromatographic properties, the electroosmotic mobility, and on the specific permeability is investigated. With a homologues series of alkylphenones it is confirmed that the hydrophobicity (methylene selectivity) of the stationary phase increases with increasing mass fraction of N-(1-adamantyl)acrylamide in the synthesis mixture., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

New rhenium(VII or III) complexes [ReO3(PTA)2][ReO4] (1) (PTA = 1,3,5-triaza-7-phosphaadamantane), [ReO3(mPTA)][ReO4]I (2) (mPTA = N-methyl-1,3,5-triaza-7-phosphaadamantane cation), [ReO3(HMT)2][ReO4] (3) (HMT = hexamethylenetetramine), [ReO3(η(2)-Tpm)(PTA)][ReO4] (4) [Tpm = hydrotris(pyrazol-1-yl)methane, HC(pz)3, pz = pyrazolyl], [ReO3(Hpz)(HMT)][ReO4] (5) (Hpz = pyrazole), [ReO(Tpms)(HMT)] (6) [Tpms = tris(pyrazol-1-yl)methanesulfonate, O3SC(pz)3(-)] and [ReCl2{N2C(O)Ph}(PTA)3] (7) have been prepared from the Re(VII) oxide Re2O7 (1-6) or, in the case of 7, by ligand exchange from the benzoyldiazenido complex [ReCl2{N2C(O)Ph}(Hpz)(PPh3)2], and characterized by IR and NMR spectroscopies, elemental analysis and electrochemical properties. Theoretical calculations at the density functional theory (DFT) level of theory indicated that the coordination of PTA to both Re(III) and Re(VII) centers by the P atom is preferable compared to the coordination by the N atom. This is interpreted in terms of the Re-PTA bond energy and hard-soft acid-base theory. The oxo-rhenium complexes 1-6 act as selective catalysts for the Baeyer-Villiger oxidation of cyclic and linear ketones (e.g., 2-methylcyclohexanone, 2-methylcyclopentanone, cyclohexanone, cyclopentanone, cyclobutanone, and 3,3-dimethyl-2-butanone or pinacolone) to the corresponding lactones or esters, in the presence of aqueous H2O2. The effects of a variety of factors are studied toward the optimization of the process.

A dyad consisting of a tripod-shaped trithiol with an adamantane core and a terminal ferrocenyl group linked through ap-phenyleneethynylene bridge was synthesized. The trithiol formed a stable self-assembled monolayer (SAM) on Au(111), wherein each molecule is bound to the surface by three-point adsorption using all sulfur atoms, with confirmation by PM-IRRAS and XPS analyses. Cyclic voltammetry of the SAM showed a line shape typical of an ideal adsorbed system, that is, a monolayer with negligible electrostatic interaction among the terminal ferrocenyl groups. Thus, a rare SAM was achieved, in which the component molecules were isolated from adjacent molecules without the coadsorption of nonelectroactive molecules.

To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.