Fr Francium

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage-derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.

Scaffolds for neuroprotection: Less than five per cent of small-molecule drugs are able to cross the blood–brain barrier (BBB). Developments in the design of compounds incorporating lipophilic, polycyclic structures have been under intense investigation in recent years. Conjugation of privileged moieties and known drug structures to these polycyclic structures has enhanced the delivery of neuroactive drugs across the BBB with subsequent neuroprotective and/or neurorestorative activity.

Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX₁R/OX₂R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.

Exploring DORAs: Orexin receptor antagonism has been identified as a new mechanism for treating insomnia with clinical proof of concept. The design of MK-6096 was partly driven by understanding the conformational properties anticipated to be favorable for high orexin receptor activity. MK-6096 represents a novel therapy for treating insomnia and other disorders related to sleep/wake dysregulation.

Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer’s disease. Previously, we found that the C-terminal fragments (CTFs), Aβ(30–42) and Aβ(31–42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ(x–42) peptides (x=28–39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12–13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the N terminus resulted in toxic peptides. Therefore, we next incorporated N-methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β-sheet formation. Focusing on Aβ(31–42), we used a two-step N-methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42-induced toxicity. First, each residue was substituted by N-Me-alanine (N-Me-A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N-Me substitution in inhibitory activity. We found that the introduction of an N-Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31–42). In particular, N-Me amino acid substitution at position 9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure-specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability.

Step by Step: A two-step N-methyl amino acid substitution method was used for a structure–activity relationship (SAR) study of Aβ(31-42). This strategy provides a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties and metabolic stability.

We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs.

Improve stability and solubility! Tripeptide prodrugs of a variety of hydroxy-containing drugs exhibiting fair chemical stability are efficiently hydrolyzed by DPPIV/CD26 to ester valyl intermediates, which spontaneously release the parent drug. A number of these prodrugs have significantly higher water solubility than their poorly soluble parent compounds.

The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.

Two multiligand coordination compounds, [Mn(AZT)₄(H₂O)₂](PA)₂·4H₂O (1) and [Co(AZT)₂(H₂O)₄](PA)₂ (2), were synthesized with 3-azido-1,2,4-triazole (AZT) as a ligand and picrate (PA) as a counteranion and characterized by elemental analysis and FTIR spectroscopy. The crystal structures were determined by single-crystal X-ray diffraction. The results show that the crystals of 1 and 2 have a triclinic space group (P) and orthorhombic space group (Pbca), respectively. Moreover, 1 and 2 have distorted octahedral structures. Their thermal decomposition mechanisms were investigated by differential scanning calorimetry and thermogravimetric analysis. The experimental data showed that the energies of combustion were approximately equal to the energies of combustion of 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX) and 1,3,5,7-tetranitro-1,3,5,7-tetraazocane (HMX). The nonisothermal kinetic parameters were studied by applying the methods of Kissinger and Ozawa. The sensitivity properties showed that 1 and 2 had a higher flame sensitivity than 2,4,6-trinitrotoluene, RDX, and HMX.

The structure of [Co(AZT)₂(H₂O)₄](PA)₂ (AZT = 3-azido-1,2,4-triazole, PA = picrate) shows that the Co^II ion is six-coordinate in a slightly distorted octahedral geometry. The energy of combustion and enthalpy of formation are 8.83 MJ kg^–1 and –3419.53 kJ mol^–1, respectively. Nonisothermal kinetic analysis indicated that the Arrhenius equation can be expressed as ln k = 15.23 – 153.3 × 10³/(RT).

When working with chemical solution deposition techniques, one of the main issues for optimal performance of CeO₂ buffer layers in coated conductors is the insufficient chemical stability of the CeO₂ layer during YBa₂Cu₃O₇ (YBCO) thermal processing. This work focusses on the morphology and nanostructure in thin CeO₂ films prepared by means of a novel aqueous synthesis route and incorporated into a Ni–W/La₂Zr₂O₇/CeO₂/YBa₂Cu₃O₇-coated conductor. Optimization of precursor chemistry and thermal processing led to a reduction in barium cerate formation. In a new precursor design, iminodiacetic acid was used as a stabilizing ligand, which resulted in an improved morphology of the buffer layer. A shelf life of more than 6 months was established by using a metal-to-ligand ratio of 1 to 5. During thermal processing, a combination of a slow calcination ramp with a high sintering ramp, short sintering dwell time and a low oxygen partial pressure during the synthesis resulted in a root mean square roughness below 3 nm for AFM analysis, a [111] to [002] ratio of 1 to 90 in X-ray diffraction and well-defined patterns in reflection high-energy electron diffraction (RHEED) analysis of the CeO₂ surface. Trifluoroacetate-YBCO was deposited on top of the CeO₂ buffer layer. Cross-section analysis with a focussed ion beam allowed us to correlate the morphology and nanostructure of the CeO₂ buffer layer with the formation of BaCeO₃ and the appearance of voids and secondary phases throughout the YBa₂Cu₃O₇ layer.

Smooth, well-textured CeO₂ buffer layers for coated conductors were synthesized by aqueous precursor formulations. The texture and morphology were characterized. Deposition of YBa₂Cu₃O₇ (YBCO) by metal–organic deposition with trifluoroacetate (TFA-MOD) and focussed ion beam analysis allowed the characterization of YBCO and the growth of secondary phases as a function of properties of the buffer layer.

A series of one-dimensional heterotrimetallic assemblies, [Cu₂Ln(L)₂(H₂O)₄][M(CN)₆]·nH₂O [Ln = Gd, M = Co (1), Fe (2), Cr (3), and Ln = La, M = Co (4), Fe (5), Cr (6)], were prepared by the reaction of a Cu₂Ln precursor complex, [Cu₂Ln(L)₂(NO₃)₃], with K₃[M(CN)₆] in water. All of the assemblies were isomorphous and formed a 1D zigzag chain, in which the [Cu₂Ln(L)₂(H₂O)₄]³⁺ and [M(CN)₆]^3– units were alternately positioned and were linked in a Cu–NC–M–CN–Cu manner. Compound 1 showed magnetic behaviour similar to that of the discrete precursor complex, [Cu₂Gd(L)₂(NO₃)₃], owing to the diamagnetic nature of the [Co^III(CN)₆]^3– unit. In the case of 2, a simple summation of the magnetic behaviour of the [Cu₂Gd(L)₂(H₂O)₄]³⁺ and [Fe(CN)₆]^3– units was observed, whereas ferromagnetic interactions were found to be operative between the Cu²⁺ and Cr³⁺ ions in compound 3. The same magnetic interactions between Cu²⁺ and M³⁺ were confirmed in compounds 4 to 6, which included the diamagnetic La³⁺ ion. The differences in the magnetic behaviours of 2 and 3 can be explained by the overlap of the d(Cu)–pπ(CN) orbitals in the bent Cu–N≡C linkage and the spin-density on the cyanide nitrogen of the [Cr(CN)₆]^3– unit.

Novel cyanide-bridged assemblies that have ordered alternate arrays of three types of paramagnetic metal centres were obtained from the reaction of preorganized heterobimetallic trinuclear complexes, [Cu₂Ln(L)₂(NO₃)₃] (Ln^III = Gd, La) and K₃[M(CN)₆] (M^III = Co, Fe, Cr). These form a 1D zigzag chain that is extended by the M^III–CN–Cu^II linkages and exhibit different magnetic behaviour, which depends on the combination of the metal ions.

Visible-light-responsive photonic structures have been prepared in alcohol solvents by using silica-modified PbS colloidal nanocrystal clusters (CNCs) as building blocks. Further modification of the PbS CNCs with a coating of silica allowed the dispersion of the particles into nonaqueous solutions. Repulsive electrostatic and solvation forces contribute to the self-assembly of the PbS@SiO₂ spheres. The core–shell particles have optical properties similar to those of CNCs, and they can also be assembled into close-packing films through simple drop-casting on silicon substrates. Embedding droplets of such a PbS@SiO₂ colloidal solution in a polymer matrix produced solid composite materials with visible-light-responsive optical properties with potential applications as sensors and optical switches.

Visible-light-responsive photonic structures have been prepared in alcohol solvents by using silica-modified PbS colloidal nanocrystal clusters as building blocks. Repulsive electrostatic and solvation forces contribute to the self-assembly of the PbS@SiO₂ spheres. Solid polymer composite films with similar light-responsive optical properties have also been produced in polymer matrices.

The new compound [Co(tren)(trenH₂)]₂[{Co(tren)}₂V₁₅Ge₆O₄₂S₆(H₂O)]·9H₂O [1, tren = tris(2-aminoethyl)amine] has been obtained under solvothermal conditions and features the unique thiogermanatovanadatopolyoxoanion[V^IV₁₅Ge^IV₆O₄₂S₆(H₂O)]^12– as the main structural motif. Compound 1 crystallizes in the monoclinic space group P2₁/c with a = 15.4711(2), b = 26.4031(4), c = 26.7213(4) Å, V = 10874.2(3) ų, and Z = 4. The [V₁₅Ge₆O₄₂S₆(H₂O)]^12– cluster anion displays the spin topology reported for the molecular magnets [V^IV₁₅As^III₆O₄₂(H₂O)]^6– and [V^IV₁₅Sb^III₆O₄₂]^6– and therefore represents a new member of the {V₁₅E₆} family, which has allowed us to study the magnetic exchange interactions between the vanadyl (d¹) groups of the geometrically frustrated central V₃ triangle, which is sandwiched between strongly antiferromagnetically coupled V₆ hexagons. The cluster shell is expanded by two {Co(tren)}²⁺-based complexes through Co–S bonds, which reduce the high negative charge of the anion. The Co²⁺ ions in the [Co(tren)(trenH₂)]⁴⁺ countercations are coordinated to one tetradentate tren and a monodentate, doubly protonated tren ligand.

The new polyoxovanadate [{Co(tren)}₂V₁₅Ge₆O₄₂S₆(H₂O)]^8– was directly synthesized from vanadate and elemental Ge and S. The cluster core [V₁₅Ge₆O₄₂S₆(H₂O)]^12– is the first V–Ge–O–S cluster and features the spin topology of the seminal molecular magnet [V₁₅As₆O₄₂(H₂O)]^6–. The cluster anion is expanded by sulfur-bound, pentacoordinate Co²⁺ complexes.