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Compounds targeting multiple proteins can have synergistic effects and are therefore of interest in medicinal chemistry. At the same time, inhibiting protein-protein interactions (PPI) is increasingly desired in the treatment of disorders or diseases. The development of non-peptidomimetic inhibitors is still a challenge. Herein we investigate macrocyclic scaffolds with one or two embedded carbohydrates (MECs) that present amino acid side chains, or related isosteres, as pharmacophoric groups. Firstly, retroscreening of the previously reported eannaphane-40 (E40, 40), a MEC presenting two pharmacophoric groups, against a set of 55 receptor-subtypes led to a finding of sub-micromolar inhibitory activity for E40 against three serotonergic isoforms (5HT 1A / 2A/2B ) as well as the Na + channel and the NK-2 receptor. We synthesised MECs with an additional pharmacophoric group compared to E40, with a view to identifying compounds where the selectivity profile was altered among the protein hits from the retroscreening. MECs were produced based on scaffolds with two monosaccharide residues, leading to the incorporation of a third pharmacophoric group. Later, homology models were prepared for four proteins (5HT 1A , 5HT 2A , NK 2 and site-2 of the sodium channel) whose 3D structure is unknown. Inverse docking of the synthesised compounds led to the selection of a new MEC (MEC-B) for protein binding assays. MEC-B was found to have its selectivity profile modulated, in line with docking prediction, compared to E40. MEC-B is dual inhibitor of both 5-HT 1A and the sodium channel with improved selectivity for these proteins compared to 5-HT 2A/2B/2C , 5-HT transporter and NK 2 receptor. Thus, a new multitargeting compound, with an improved selectivity profile was identified, based on a MEC peptidomimetic scaffold., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Invited for the cover of this issue are Paul V. Murphy and co-workers at the National University of Ireland Galway (NUI Galway) and Warsaw University. The image depicts MGSTA-6 giving a stop signal to tumour cells that are on the move. Read the full text of the article at 10.1002/chem.201502861., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The potentially hexadentate mixed-donor cage ligand 1-methyl-8-amino-3,13,16-trithia-6,10,19-triazabicyclo[6.6.6]eicosane (AMME-N(3)S(3)sar; sar=sarcophagine) displays variable coordination modes in a complex with copper(II). In the absence of coordinating anions, the ligand adopts a conventional hexadentate N(3)S(3) binding mode in the complex [Cu(AMME-N(3)S(3)sar)](ClO(4))(2) that is typical of cage ligands. This structure was determined by X-ray crystallography and solution spectroscopy (EPR and NIR UV/Vis). However, in the presence of bromide ions in DMSO, clean conversion to a five-coordinate bromido complex [Cu(AMME-N(3)S(3)sar)Br](+) is observed that features a novel tetradentate (N(2)S(2))-coordinated form of the cage ligand. This copper(II) complex has also been characterized by X-ray crystallography and solution spectroscopy. The mechanism of the reversible interconversion between the six- and five-coordinated copper(II) complexes has been studied and the reaction has been resolved into two steps; the rate of the first is linearly dependent on bromide ion concentration and the second is bromide independent. Electrochemistry of both [Cu(AMME-N(3)S(3)sar)](2+) and [Cu(AMME-N(3)S(3)sar)Br](+) in DMSO shows that upon reduction to the monovalent state, they share a common five-coordinated form in which the ligand is bound to copper in a tetradentate form exclusively, regardless of whether a six- or five-coordinated copper(II) complex is the precursor.

Marine derived cyclic peptides have inspired chemists for decades as the cavitand architecture can be compared with macrocyclic ligands, and hence easily conceived as mediators of metal-ion transport. Lissoclinamide 5 and ascidiacyclamide are two such cyclic peptides that have received much attention both for their metal ion complexation properties and biological activity; the metal ion binding properties of mimics of these two systems have been reported. Reported herein is a computational study aimed at evaluating the stability, and potential for copper(ii) ion binding by lissoclinamide 5 mimics that substitute the naturally occurring 4-carboxy-1,3-thiazole units for novel valine- and phenylalanine-derived 1,2,4-thiadiazole units. Our results suggest that one lissoclinamide 5 mimic, 1,2,4-thiadiazole (TDA)-lissoclinamide 9 , may be capable of forming a complex with one CuII ion, [Cu(9 -H)(H2O)]+. A complex with two CuII ions, [Cu2(9 -H)(μ-OH)]2+, was also considered. These results set the stage for synthetic and experimental metal binding studies. 1,2,4-Thiadiazole-lissoclinamide 9 , a next generation mimic design, was evaluated in silico for metal binding aptitude towards CuII ions. DFT calculations suggest that TDA-lissoclinamide may be capable of forming a complex with one CuII ion, [Cu(9 -H)(H2O)]+. These results underpin future synthetic and experimental metal binding studies. [ABSTRACT FROM AUTHOR]

Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal-ion transport. The study presented herein investigated the metal chelation of non-natural heteroatom-interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI-lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti-cancer properties demonstrated that the biological activity of HI-lissoclinamide 5 against T24 bladder cells was eleven-fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity. [ABSTRACT FROM AUTHOR]

The synthesis of three macrotriazoles that are analogues of migrastatin is reported. The synthesis is based on copper(I)- and ruthenium-catalyzed azide-alkyne cycloaddition reactions. The enantiopure terminal alkyne derivatives were prepared by using the Trost desymmetrization, Brown alkoxyallylation and an efficient Colvin reaction. Biological evaluation of the products revealed a promising efficiency in reducing the ability of MDA-MB-361 cell lines to migrate. [ABSTRACT FROM AUTHOR]

Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure-activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa-Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9-methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects. [ABSTRACT FROM AUTHOR]

The kinetics and mechanism of the redox reaction between [FeII(CN)6]4−and the macrocyclic ligand complex [CrClL15]2+(L15= 6-methyl-1,4,8,12-tetraazacyclopentadecane-6-amine) has been studied at different pH values. In acidic solution, the expected redox process occurs with no formation of any of the possible CrIII/FeIImixed valence complexes, as those seen for the CoIIIspecies of the same family, due to the enhanced lability of the CrIIspecies formed on FeIIto FeIIIoxidation. In alkaline conditions, the formation of the complex [Cr(L15)(OH)2]+takes place as an initial step that precedes a simple substitution process producing the expected cyano-bridged CrIII/FeIIcomplex. In this species the potentially pentadentate ligand, L15, has a tetradentate coordination mode with a protonated exocyclic primary amine group and the redox potential is shifted to more negative values, thus disfavouring a redox driven reaction; the equivalent complex [CrCl(HL14)(H2O)]3+(L14= 6-methyl-1,4,8,11-tetraazacyclotetradecane-6-amine) has been prepared by the same method and characterized by X-ray crystallography. The final [FeII(CN)6]4−substituted complex, [{(HL15)(OH)CrIIINC}FeII(CN)5]−shows pKavalues of 3.8 and 7.4, as expected for the aqua and amino ligands, respectively. Its characterization indicated its Class IImixed valence character with a very intense MMCT band at 350 nm showing a much larger extinction coefficient than that observed for the CoIIIcomplexes of the same family. This fact is in good agreement with the much larger CrIII–FeII(t2g–t2g) coupling through cyanide bridging ligands expected for these complexes. The fully mixed metal/valence/ligand trimetallic complex [{(HL15)(OH)CrIIINC}{L13CoIIINC}FeII(CN)4]2+has been prepared following the same procedures and the results are comparable. The final complex has the same Class IImixed valence character and its electronic spectrum shows the characteristics of both the FeII-to-CrIIIand FeII-to-CoIIICT bands. The study allows the application of the redox and/or substitutionally driven methodology, already described and kinetically designed, for the preparation of discrete mixed valence complexes of inert centres, so avoiding the unpredictable nature of other approaches seen in the past. [ABSTRACT FROM AUTHOR]

Abstract: A thiophene-functionalised macrocyclic ligand trans-6,13-dimethyl-6-((thiophen-3-ylmethyl)amino)-1,4,8,11-tetraazacyclotetradecane-13-amine (L1) has been prepared and complexed with CoIII. The ligand L1 binds as a pentadentate in the crystallographically characterised complexes [CoL1(OAc)](ClO4)2 and [CoL1Cl]Cl2. Electro-copolymerisation of [CoL1Cl]Cl2 with 3,4-ethylenedioxythiophene (EDOT) in a 1:2 ratio on a preformed poly-3,4-ethylenedioxythiophene (PEDOT) film resulted in metal–polymer hybrid films of high quality, consistency and uniformity in appearance. The copolymerised films were characterised by XPS indicating a 1:11 ratio of incorporation of complex to EDOT. Electrochemistry of the Co-PEDOT film (cast on an indium-doped tin oxide working electrode) in water revealed a CoIII/II redox couple at a potential ca. −600mV (vs Ag/AgCl) which is similar to that seen in solution for the monomeric aqua complex [CoL1(OH2)]3+. [Copyright &y& Elsevier]

A selection of nine macrocyclic FeIII/II and CoIII/II transition metal complexes has been chosen to serve as a universal set of mediator-titrants in redox potentiometry of protein samples. The potential range spanned by these mediators is approximately from +300 to −700 mV vs the normal hydrogen electrode, which covers the range of most protein redox potentials accessible in aqueous solution. The complexes employed exhibit stability in both their oxidized and their reduced forms as well as pH-independent redox potentials within the range 6 < pH < 9. The mediators were also chosen on the basis of their very weak visible absorption maxima in both oxidation states, which will enable (for the first time) optical redox potentiometric titrations of proteins with relatively low extinction coefficients. This has previously been impractical with organic mediators, such as indoles, viologens and quinones, whose optical spectra interfere strongly with those of the protein. [ABSTRACT FROM AUTHOR]

The rate of electronic energy transfer (EET) between a naphthalene donor and an anthracene acceptor in [ZnL³](ClO4)2 and [ZnL4](ClO4)2 was determined by time-resolved fluorescence measurements, where L³ and L4 are the geometrical isomers of 6-[(anthracen-9-ylmethyl)amino]-trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-13-amine (L²), substituted with either a naphthalene-1-ylmethyl or naphthalen-2-ylmethyl donor, respectively. The energy-transfer rate constant, kEET, was determined to be (0.92 ± 0.02) ⊗ 109 s-1 for the naphthalen-1-ylmethyl-substituted isomer, while that for the naphthalen-2-ylmethyl-substituted isomer is somewhat faster, with kEET = (1.31 ± 0.01) ⊗ 109 s-1. The solid-state structure of [ZnL³Cl]ClO4 has been determined, and using molecular modeling calculations, the likely distributions of solution conformations in CH3CN have been evaluated for both complexes. The calculated conformational distributions in the common trans-III N-based isomeric form gave Förster EET rate constants that account for the differences observed and are in excellent agreement with the experimental values. It is shown that the full range of conformers must be considered to accurately reproduce the observed EET kinetics. [ABSTRACT FROM AUTHOR]

Abstract: The crystal structure of an amphiphilic macrocycle [Velasco-Torrijos, T.; Murphy, P. V., Tetrahedron: Asymmetry 2005, 16, 261–272] derived from saccharides shows extensive hydrogen-bonding networks, including participation of water, that may have relevance for the modelling of carbohydrate–carbohydrate recognition at cell–cell interfaces. The structure may provide a basis for understanding the binding of the macrocycle to hydrophobic probes. [Copyright &y& Elsevier]

The pendent-arm macrocyclic hexaamine trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L) may coordinate in tetra-, penta- or hexadentate modes, depending on the metal ion and the synthetic procedure. We report here the crystal structures of two pseudo-octahedral cobalt(III) complexes of L, namely sodium trans-cyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine)cobalt(III) triperchlorate, Na[Co(CN)(C13H30N6)](ClO4)3 or Na{trans-[CoL(CN)]}(ClO4)3, (I), where L is coordinated as a pentadentate ligand, and trans-dicyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine)cobalt(III) trans-dicyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diaminium)cobalt(III) tetraperchlorate tetrahydrate, [Co(CN)2(C14H32N6)][Co(CN)2(C14H30N6)](ClO4)4·-4H2O or trans-[CoL(CN)2]trans-[Co(H2L)(CN)2](ClO4)4·-4H2O, (II), where the ligand binds in a tetradentate mode, with the remaining coordination sites being filled by C-bound cyano ligands. In (I), the secondary amine Co—N bond lengths lie within the range 1.944 (3)–1.969 (3) Å, while the trans influence of the cyano ligand lengthens the Co—N bond length of the coordinated primary amine [Co—N = 1.986 (3) Å]. The Co—CN bond length is 1.899 (3) Å. The complex cations in (II) are each located on centres of symmetry. The Co—N bond lengths in both cations are somewhat longer than in (I) and span a narrow range [1.972 (3)–1.982 (3) Å]. The two independent Co—CN bond lengths are similar [1.918 (4) and 1.926 (4) Å] but significantly longer than in the structure of (I), again a consequence of the trans influence of each cyano ligand. [ABSTRACT FROM AUTHOR]

Abstract: The crystal structure of the Cu(II) perchlorate complex of a functionalised bis(macrocycle) ligand, where the individual macrocycle units are of the cyclam type and adopt the trans-III configuration, is analysed in terms of its possible relationship to those of bis(macrocycle) complexes possessing anti-viral activity. To cite this article: P.V. Bernhardt et al., C. R. Chimie 8 (2005) . [Copyright &y& Elsevier]

Reaction between ethane-1,2-diamine and 3,3'-dichloropivalic acid results in different, isomeric tetra-amine derivatives, one a tetraamino carboxylic acid and the other a carboxamidotriamino alcohol, depending upon reaction conditions. Intended conversion of the Cu(II) complex of the former to a cyclam-like macrocycle through reaction with nitroethane and formaldehyde results in isolation of derivatives of both the former and the latter. This can be rationalized by assuming the intermediacy of an azetidinone, a species similar to that seen in simpler reactions of dichloropivalates. A single reaction thereby provides pendent-arm macrocycles where one has an electrophilic and the other a nucleophilic substituent. Parallel chemistry is not seen in the reaction between propane-1,3-diamine and 3,3'dichloropivalate. [ABSTRACT FROM AUTHOR]

A novel series of triazine-appended macrocyclic complexes has been investigated as potential hydrogen bonding receptors for complementarily disposed heterocycles. Cocrystallization of a melamine-appended azacyclam complex of Cu[sup II] has been achieved with barbitone, the barbiturate anion and thymine. In each case, a complementary BAD/ADA hydrogen bonding motif between the melamine group and the heterocycle has been identified by X-ray crystallography. Electrochemical studies of the copper macrocycles in both nonaqueous and aqueous solution show anodic shifts of the Cu[sup II/I] redox couple of more than 60 mV upon addition of guest molecules with matching H-bonding motifs. The Zn[sup II] analogues have been synthesized via transmetalation of the Cu[sup II] complex, and their guest binding properties investigated by NMR spectroscopy. ¹H NMR shifts of up to 0.8 ppm were observed upon addition of guest, and stability constants are similar to those obtained electrochemically. [ABSTRACT FROM AUTHOR]

Investigates the intramolecular electronic energy transfer in bichromophoric macrocyclic complexes. Oxidation of proximate amine lone pairs; Characteristic of the chromophore; Mechanism of the energy transfer in the zinc complexes.

Examines the application of carbon-substituted macrocycles as bifunctional chelating agents in radioimmunotherapy. Disadvantages on the use of isotope I as a therapeutic radioisotope; Consideration of copper isotopes in radioimmunotherapy; Variation in the reactivity of substituted benzaldehydes.

Reports on the synthesis of tetraazamacrocyclic complexes containing 2-substituted imidazolidine rings. Study of their coordination chemistry with copper(II); X-ray crystal structure analyses of three of these complexes; Trends in their electron paramagnetic resonance spectroscopy and visible spectroscopy.

Analyzes the electrochemistry of cobalt(C0)(III/II) hexaamines. Nature of the macrocyclic cobalt hexaamines; Reoxidation of CoII species; Stability of the cobalt complexes; Use of cobalt complex for the reduction of protons to dihydrogen.

Cites an experimental study which investigated the use of aminotriazines in the synthesis of macrocyclic compounds. Details on the crystal structures and physical properties of the compounds; Analysis of the compounds; Conclusions drawn from the results of the study.

Presents a study in which macrocycle (trans-5(R), 7(R), 12(S), 14(S))-tetramethyl-6,13-dinitro-1,4,8,11-tetraazacy-clotetradeca ne (L), were synthesized stereoselectively in good yield by a reaction of bis(ethane-1,2-diamine)copper(III) and acetaldehyde and nitromethane in methanol. Methodoloy used to conduct the study; Information on experiments conducted; Findings of the study.

Reports on the syntheses of the macrocyclic (hexaamine)cobalt(III/II) complexes. Characterization of the complexes; Structural and electron self-exchange rate variations in the isomeric complexes; X-ray crystal structural analyses of the macrocyclic complex.

Presents information on investigations of the potentially hexadentate isomeric macrocycle trans-and cis-6,13,dimethyl-1,4,8,11,-tetraazacyclotetradecane-6,13-diamin e (L5 and L6). Unexpected conformational behavior; Experimental section of the investigations; X-ray crystal structure analyses.

Tumour cell migration can be stopped by small molecules such as migrastatin, a natural product that inhibits tumour cell migration (μM range) in vitro. In their Full Paper on page 18109 ff., P. Murphy et al. describe the synthesis and structure – activity studies of migrastatin and its analogues. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound ‐ healing (scratch) and Boyden chamber assays, with one analogue showing low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects. [ABSTRACT FROM AUTHOR]

Like the larger nonplanar Möbius rings, porphyrinoid aromaticity is not due primarily to the macrocyclic p conjugation of the corresponding annulene perimeters. The block-localized wave function (BLW)-derived aromatic stabilization energies (ASE) of several porphyrinoids reveal that, on a per atom basis, the appended 6p electron heterocycles of porphyrinoids confer aromaticity much more effectively than the macrocyclic 4n+2 π electron conjugations. There is no direct relationship between thermochemical stability of porphyrinoids and their macrocyclic 4n or 4n+2 π electron counts. Porphyrinoids having an "antiaromatic" macrocyclic 4n+2 π electron conjugation pathway (e.g., 4) as well as those having no macrocyclic conjugation (e.g., 9) can be stabilized by aromaticity. Computed nucleus independent chemical shifts (NICS) and the anisotropy of the induced current density (ACID) disclose the intricate local versus macrocyclic circulation interplay for several porphyrinoids. [ABSTRACT FROM AUTHOR]

A build–couple–pairstrategy, including double-reductiveamination macrocyclization, has been used to generate decorated macrocycles(eannaphanes) with an embedded triazole and monosaccharide. Biologicalscreening led to the identification of an inducer of apoptosis inleukemic cells, which acts at least partially as a 5-HT2 antagonist. [ABSTRACT FROM AUTHOR]

Abstract: Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin. [Copyright &y& Elsevier]

The new cyanido-bridged mixed valent FeII/CoIIImacrocyclic complexes [L2CoIII(μ-NC)FeII(CN)5]-and trans-[L2CoIII(μ-NC)FeII(CN)4(μ-CN)CoIIIL2]2+have been prepared and characterized spectroscopically. The trinuclear complex trans-[L2Co(μ-NC)Fe(CN)4(μ-CN)CoL2](ClO4)2·11H2O has been characterized crystallographically. The di- and trinuclear complexes exhibit metal-to-metal charge transfer transitions characteristic of Class II mixed valent chromophores and their redox and spectroscopic properties have been analyzed by Hush theory. The thiophene group attached to the macrocycle L2in these complexes may serve as a precursor to conducting polythiophene-based hybrid materials incorporating redox active transition metal ions. [ABSTRACT FROM AUTHOR]

Synthesis of compounds with characteristics of natural products are required to increase the diversity and biological relevance of compounds for screening. These include new frameworks/scaffolds, with multiple stereogenic centres and various functional groups. Carbohydrates are renewable, readily available and have stereochemical diversity and functionality. Herein, building blocks derived from monosaccharides with alkene, alkyne and organic azide functional groups are used. The build-couple-pair strategy of diversity oriented synthesis is employed taking advantage of RuAAC, CuAAC and thermally promoted azide-alkyne cycloadditions, allylic azide (Winstein) rearrangement and ring closing metathesis, leading to polyhydroxylated small, medium and macrocyclic ring containing scaffolds. There is potential to graft appendages (e.g. pharmacophoric groups) to further increase diversity of compounds available for screening, or to consider the scaffolds in ligand design. Image 1 [ABSTRACT FROM AUTHOR]