Design, synthesis and evaluation of RGD peptidomimetic - Gold nanostar conjugates as M21 cell adhesion inhibitors.

Effective targeting of αvß3 integrin is of high relevance in cancer research as this protein is overexpressed on several types of tumor cells, making such receptor ideal for the development of therapeutics and of diagnostic imaging agents. In this paper, the synthesis of a novel functionalized triazole-based RGD peptidomimetic and its covalent conjugation on pegylated gold nanostars is reported. These highly stable nanoconstructs showed a multivalent effect in binding αvß3 integrin receptors and proved to inhibit M21 cell adhesion at 25 pM concentration. Thanks to their peculiar surface plasmon resonance in the "NIR transparent window", targeted gold nanostars may represent a promising agent for anticancer multi-modality treatments. 2009 Elsevier Ltd. All rights reserved.

Design and Synthesis of Novel Raman Reporters for Bioorthogonal SERS Nanoprobes Engineering.

Surface-enhanced Raman spectroscopy (SERS) exploiting Raman reporter-labeled nanoparticles (RR@NPs) represents a powerful tool for the improvement of optical bio-assays due to RRs' narrow peaks, SERS high sensitivity, and potential for multiplexing. In the present work, starting from low-cost and highly available raw materials such as cysteamine and substituted benzoic acids, novel bioorthogonal RRs, characterized by strong signal (103 counts with FWHM < 15 cm−1) in the biological Raman-silent region (>2000 cm−1), RRs are synthesized by implementing a versatile, modular, and straightforward method with high yields and requiring three steps lasting 18 h, thus overcoming the limitations of current reported procedures. The resulting RRs' chemical structure has SH-pendant groups exploited for covalent conjugation to high anisotropic gold-NPs. RR@NPs constructs work as SERS nanoprobes demonstrating high colloidal stability while retaining NPs' physical and vibrational properties, with a limit of detection down to 60 pM. RR@NPs constructs expose carboxylic moieties for further self-assembling of biomolecules (such as antibodies), conferring tagging capabilities to the SERS nanoprobes even in heterogeneous samples, as demonstrated with in vitro experiments by transmembrane proteins tagging in cell cultures. Finally, thanks to their non-overlapping spectra, we envision and preliminary prove the possibility of exploiting RR@NPs constructs simultaneously, aiming at improving current SERS-based multiplexing bioassays.

Synthesis of morpholine derivatives using the Castagnoli-Cushman reaction as BACE1 inhibitors: Unexpected binding activity of cyclic thioamides.

The Castagnoli-Cushman reaction between diglycolic anhydride and imines was applied for the synthesis of morpholine derivatives containing a thioamide or an amidino group. Enzyme inhibition assays towards BACE1 revealed an unexpected role of the cyclic thioamide group in providing inhibition in the micromolar range. Molecular docking calculations showed the thioamido group interacting with catalytic aspartic acid, and calculated BBB permeability indicated this molecular scaffold as a promising hit for further optimization.

Combination of multicomponent KA2 and Pauson-Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones.

The Cu-catalyzed multicomponent ketone-amine-alkyne (KA2) reaction was combined with a Pauson-Khand cycloaddition to give access of unprecedented constrained spirocyclic pyrrolocyclopentenone derivatives following a DOS couple-pair approach. The polyfunctional molecular scaffolds were tested on the cyclopentenone reactivity to further expand the skeletal diversity, demonstrating the utility of this combined approach in generating novel spiro compounds as starting material for the generation of chemical libraries. The chemoinformatics characterization of the newly-synthesized molecules gave evidence about structural and physicochemical properties with respect to a set of blockbuster drugs, and showed that such scaffolds are drug-like but more spherical and three-dimensional in character than the drugs.

Identification of highly potent and selective MMP2 inhibitors addressing the S1' subsite with d-proline-based compounds.

MMP2 and MMP9, also called gelatinases, play a primary role in the angiogenic switch, as a fundamental step of tumor progression, and show high degree of structural similarity. Clinically successful gelatinase inhibitors need to be highly selective as opposite effects have been found for the two enzymes, and the S1' subsite is the major driver to attain selective and potent inhibitors. The synthesis of d-proline-derived hydroxamic acids containing diverse appendages at the amino group, varying in length and decoration allowed to give insight on the MMP2/MMP9 selectivity around the S1' subsite, resulting in the identification of sub-nanomolar compounds with high selectivity up to 730. Molecular docking studies revealed the existence of an additional hydrophobic channel at the bottom of S1' subsite for MMP2 enzyme useful to drive selectivity towards such gelatinase.

Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors.

Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.

Identification of Novel Human Breast Carcinoma (MDA-MB-231) Cell Growth Modulators from a Carbohydrate-Based Diversity Oriented Synthesis Library.

The application of a cell-based growth inhibition on a library of skeletally different glycomimetics allowed for the selection of a hexahydro-2H-furo[3,2-b][1,4]oxazine compound as candidate inhibitors of MDA-MB-231 cell growth. Subsequent synthesis of analogue compounds and preliminary biological studies validated the selection of a valuable hit compound with a novel polyhydroxylated structure for the modulation of the breast carcinoma cell cycle mechanism.

Two-step one-pot synthesis of dihydropyrazinones as Xaa-Ser dipeptide isosteres through morpholine acetal rearrangement.

The synthesis of the uncommon dihydropyrazinone ring was accomplished by a two-step one pot process taking advantage of the ring rearrangement of N-acylated morpholine acetal derived from serine under acidic treatment in the presence of 2,6-lutidine. The mechanism involves an N-acyl iminium intermediate resulting from morpholine acetal ring opening, which occurs after a nucleophilic attack of the amino acid nitrogen atom to the acetal carbonyl atom. X-Ray diffraction analysis of the dihydropyrazinone, which may be exploited as a constrained Xaa-Ser dipeptide isostere, showed a planar assembly and the internal side-chain in axial orientation with respect to the cyclic molecular scaffold.

Cotton fabric functionalisation with menthol/PCL micro- and nano-capsules for comfort improvement.

OBJECTIVE: Cotton functionalisation with poly-ɛ-caprolactone (PCL) micro- and nano-capsules containing menthol was carried out with the aim of introducing a long-lasting refreshing sensation. MATERIALS AND METHODS: The preparation of the polymer micro- and nano-capsules was carried out by solvent displacement technique. A confined impinging jets mixer was used in order to ensure fast mixing and generate a homogeneous environment where PCL and menthol can self-assemble. RESULTS: The micro- and nano-capsules and the functionalised fabrics were characterised by means of DSC, FT-IR spectroscopy and SEM imaging. Micro- and nano-capsules of different size, from about 200 to about 1200 nm, were obtained varying menthol to PCL ratio (from 0.76 to 8), overall concentration and flow rate (i.e. mixing conditions). The inclusion of menthol was confirmed by DSC analysis. DISCUSSION AND CONCLUSION: A patch test was carried out by 10 volunteers. Micro-capsules were found to be effective in conferring the fabric a refreshing sensation without altering skin physiology.

Measurement of Water Uptake and States in Nafion Membranes Using Humidity-Controlled Terahertz Time-Domain Spectroscopy.

Perfluorinated sulfonic acid ionomers are well known for their unique water uptake properties and chemical/mechanical stability. Understanding their performance-stability trade-offs is key to realizing membranes with optimal properties. Terahertz time-domain spectroscopy has been demonstrated to resolve water states inside industrially relevant membranes, producing qualitatively agreeable results to conventional gravimetric analysis and prior demonstrations. Using the proposed humidity-controlled terahertz time-domain spectroscopy, here we quantify this detailed water information inside commercially available Nafion membranes at various humidities for direct comparison against literature values from dynamic vapor sorption, differential scanning calorimetry, and Fourier transform infrared spectroscopy on selected samples. Using this technique therefore opens up opportunities for rapid future parameter space investigation for membrane optimization.

Near-Field Spectroscopy of Individual Asymmetric Split-Ring Terahertz Resonators.

Metamaterial resonators have become an efficient and versatile platform in the terahertz frequency range, finding applications in integrated optical devices, such as active modulators and detectors, and in fundamental research, e.g., ultrastrong light-matter investigations. Despite their growing use, characterization of modes supported by these subwavelength elements has proven to be challenging and it still relies on indirect observation of the collective far-field transmission/reflection properties of resonator arrays. Here, we present a broadband time-domain spectroscopic investigation of individual metamaterial resonators via a THz aperture scanning near-field microscope (a-SNOM). The time-domain a-SNOM allows the mapping and quantitative analysis of strongly confined modes supported by the resonators. In particular, a cross-polarized configuration presented here allows an investigation of weakly radiative modes. These results hold great potential to advance future metamaterial-based optoelectronic platforms for fundamental research in THz photonics.

Terahertz confocal microscopy with a quantum cascade laser source.

We report on the implementation of a confocal microscopy system based on a 2.9 THz quantum cascade laser source. Lateral and axial resolutions better than 70 µm and 400 µm, respectively, are achieved, with a large contrast enhancement compared to the non-confocal arrangement. The capability of resolving overlapping objects lying on different longitudinal planes is also clearly demonstrated.

An in-plane photoelectric effect in two-dimensional electron systems for terahertz detection.

Many mid- and far-infrared semiconductor photodetectors rely on a photonic response, when the photon energy is large enough to excite and extract electrons due to optical transitions. Toward the terahertz range with photon energies of a few milli-electron volts, classical mechanisms are used instead. This is the case in two-dimensional electron systems, where terahertz detection is dominated by plasmonic mixing and by scattering-based thermal phenomena. Here, we report on the observation of a quantum, collision-free phenomenon that yields a giant photoresponse at terahertz frequencies (1.9 THz), more than 10-fold as large as expected from plasmonic mixing. We artificially create an electrically tunable potential step within a degenerate two-dimensional electron gas. When exposed to terahertz radiation, electrons absorb photons and generate a large photocurrent under zero source-drain bias. The observed phenomenon, which we call the "in-plane photoelectric effect," provides an opportunity for efficient direct detection across the entire terahertz range.

Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II.

A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.

Active Terahertz Modulator and Slow Light Metamaterial Devices with Hybrid Graphene-Superconductor Photonic Integrated Circuits.

Metamaterial photonic integrated circuits with arrays of hybrid graphene-superconductor coupled split-ring resonators (SRR) capable of modulating and slowing down terahertz (THz) light are introduced and proposed. The hybrid device's optical responses, such as electromagnetic-induced transparency (EIT) and group delay, can be modulated in several ways. First, it is modulated electrically by changing the conductivity and carrier concentrations in graphene. Alternatively, the optical response can be modified by acting on the device temperature sensitivity by switching Nb from a lossy normal phase to a low-loss quantum mechanical phase below the transition temperature (Tc) of Nb. Maximum modulation depths of 57.3% and 97.61% are achieved for EIT and group delay at the THz transmission window, respectively. A comparison is carried out between the Nb-graphene-Nb coupled SRR-based devices with those of Au-graphene-Au SRRs, and significant enhancements of the THz transmission, group delay, and EIT responses are observed when Nb is in the quantum mechanical phase. Such hybrid devices with their reasonably large and tunable slow light bandwidth pave the way for the realization of active optoelectronic modulators, filters, phase shifters, and slow light devices for applications in chip-scale future communication and computation systems.

Diversity-Oriented Synthesis and Chemoinformatic Analysis of the Molecular Diversity of sp3-Rich Morpholine Peptidomimetics.

Diversity-Oriented Synthesis (DOS) consists of generating structurally diverse compounds from a complexity-generating reaction followed by cyclization steps and appendage diversity. DOS has gathered interest to systematically explore the chemical space by generating high-quality small-molecule collections as probes to investigate biological pathways. The generation of heterocycles using amino acid and sugar derivatives as building blocks is a powerful approach to access chemical and geometrical diversity thanks to the high number of stereocenters and the polyfunctionality of such compounds. Our efforts in this field are focused on the generation of diversity-oriented molecules of peptidomimetic nature as a tool addressing protein-protein interactions, taking advantage of amino acid- and sugar-derived polyfunctional building blocks to be applied in couple-pair synthetic approaches. In this paper, the combination of diversity-oriented synthesis and chemoinformatics analysis of chemical space and molecular diversity of heterocyclic peptidomimetics are reported, with particular interest toward carbohydrate- and amino acid-derived morpholine scaffolds with a higher fraction of sp3 carbon atoms. Also, the chemoinformatic analysis of chemical space and molecular diversity of 186 morpholine peptidomimetics is outlined.

Contactless graphene conductivity mapping on a wide range of substrates with terahertz time-domain reflection spectroscopy.

We demonstrate how terahertz time-domain spectroscopy (THz-TDS) operating in reflection geometry can be used for quantitative conductivity mapping of large area chemical vapour deposited graphene films on sapphire, silicon dioxide/silicon and germanium. We validate the technique against measurements performed with previously established conventional transmission based THz-TDS and are able to resolve conductivity changes in response to induced back-gate voltages. Compared to the transmission geometry, measurement in reflection mode requires careful alignment and complex analysis, but circumvents the need of a terahertz transparent substrate, potentially enabling fast, contactless, in-line characterisation of graphene films on non-insulating substrates such as germanium.

Continuous-wave laser operation of a dipole antenna terahertz microresonator.

Resonators and the way they couple to external radiation rely on very different concepts if one considers devices belonging to the photonic and electronic worlds. The terahertz frequency range, however, provides intriguing possibilities for the development of hybrid technologies that merge ideas from both fields in novel functional designs. In this paper, we show that high-quality, subwavelength, whispering-gallery lasers can be combined to form a linear dipole antenna, which creates a very efficient, low-threshold laser emission in a collimated beam pattern. For this purpose, we employ a terahertz quantum-cascade active region patterned into two 19-µm-radius microdisks coupled by a suspended metallic bridge, which simultaneously acts as an inductive antenna and produces the dipole symmetry of the lasing mode. Continuous-wave vertical emission is demonstrated at approximately 3.5 THz in a very regular, low-divergence (±10°) beam, with a high slope efficiency of at least 160 mW A-1 and a mere 6 mA of threshold current, which is ensured by the ultra-small resonator size (VRES/λ3≈10-2). The extremely low power consumption and the superior beam brightness make this concept very promising for the development of miniaturized and portable THz sources to be used in the field for imaging and sensing applications as well as for exploring novel optomechanical intracavity effects.

Optical waveguides in Sn(2)P(2)S(6) by low fluence MeV He+ ion implantation.

Planar waveguides in nonlinear optical crystals of Sn(2)P(2)S(6) have been produced by He+ ion implantation. The effective indices of the waveguide have been determined and refractive index profiles have been evaluated for the indices along all three principal axes of the optical indicatrix. The depth of the induced optical barrier is n1 = -0.07, n2 = -0.07 and n3 = -0.09 at lambda = 0.633 microm for a fluence Phi = 0.5x10(15)ions/cm(2). Propagation losses for hybrid-n(1) modes are alpha approximately 10dB/cm.