Macrocyclic Structure Research Articles

Around the macrolide – Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation

The aim of this study was to investigate lipophilicity and cellular accumulation of rationally designed azithromycin and clarithromycin derivatives at the molecular level. The effect of substitution site and substituent properties on a global physico-chemical profile and cellular accumulation of investigated compounds was studied using calculated structural parameters as well as experimentally determined lipophilicity. In silico models based on the 3D structure of molecules were generated to investigate conformational effect on studied properties and to enable prediction of lipophilicity and cellular accumulation for this class of molecules based on non-empirical parameters. The applicability of developed models was explored on a validation and test sets and compared with previously developed empirical models.

Dinuclear organotin(IV) coordination polymers derived from Schiff bases with l-aspartic acid

Reaction of sodium 2-((E)-((Z)-4-hydroxypent-3-en-2-ylidene)amino)succinate and sodium (E)-2-((1-(2-hydroxyphenyl)ethylidene)amino)succinate (L1HNa2 and L2HNa2) in a 1:2 M ratio with Bz2SnCl2 in methanol gave dinuclear diorganotin(IV) complexes of composition [Bz2Sn(Lx)SnBz2Cl] (Lx = L1 (1) and L2 (2)). Reaction of L2HNa2 and Bz3SnCl (1:2) in anhydrous toluene under reflux conditions yielded the analogous chlorine-free product of composition [Bz2Sn(L2)SnBz3] (3) via cleavage of a Sn-C bond for one of the triorganotin precursor equivalents with elimination of toluene. In addition, the tributyltin(IV) compounds of composition [Bu3Sn(LxH)SnBu3] (Lx = L2 (4) and L3 (5)) were prepared in a single-step transformation by combining equimolar proportions of (Bu3Sn)2O, (S)-2-aminosuccinic acid and 2'-hydroxyacetophenone/2-hydroxybenzaldehyde in anhydrous methanol. The structures of the organotin(IV) compounds in solution were assessed using 1H, 13C and 119Sn NMR spectroscopic techniques, while the molecular structures of 1–5 were analyzed by single-crystal X-ray diffraction. In the solid state, complexes 1-3 exhibit one-dimensional coordination polymers with alternate six- and seven-coordinate tin atoms embedded in distorted monocapped trigonal-bipyramidal (1-2)/octahedral (3) and pentagonal-bipyramidal (1-2)/bicapped trigonal-bipyramidal (3) coordination environments. On the contrary, compounds 4–5 are two-dimensional coordination polymers based on 30-membered tetranuclear macrocyclic ring structures, in which the tin atoms comprise distorted trigonal-bipyramidal coordination polyhedra. However, in solution the polymeric structures of 1–5 dissociate to give dinuclear complexes, even in non-coordinating solvents such as chloroform.

Chalcogen Bonding Macrocycles and [2]Rotaxanes for Anion Recognition.

Electron-deficient heavy chalcogen atoms contain Lewis acidic σ-holes which are able to form attractive supramolecular interactions, known as chalcogen bonding (ChB), with Lewis bases. However, their potential in solution-phase anion binding applications is only just beginning to be realized in simple acyclic systems. Herein, we explore the 5-(methylchalcogeno)-1,2,3-triazole (chalcogen = Se, Te) motif as a novel ChB donor for anion binding. Other than being chemically robust enough to be incorporated into macrocyclic structures, thereby significantly expanding the scope and complexity of ChB host systems, we also demonstrate, by 1H NMR and DFT calculations, that the chalcogen atoms oriented within the macrocycle cavity are able to chelate copper(I) endotopically. Exploiting this property, the first examples of mechanically interlocked [2]rotaxanes containing ChB-donor groups are prepared via an active metal template strategy. Solution-phase 1H NMR and molecular modeling studies provide compelling evidence for the dominant influence of ChB in anion binding by these interlocked host systems. In addition, unprecedented charge-assisted ChB-mediated anion binding was also studied in aqueous solvent mixtures, which revealed considerable differences in anion recognition behavior in comparison with chalcogen-free host analogues. Moreover, DFT calculations and molecular dynamics simulations in aqueous solvent mixtures indicate that the selectivity is determined by the different hydrophilic characters of the anions allied to the hydration of the binding units in the presence of the anions. Exploiting the NMR-active nuclei of the ChB-donor chalcogen atoms, heteronuclear 77Se and 125Te NMR were used to directly study how anion recognition influences the local electronic environment of the chalcogen atoms in the mechanically bonded rotaxane binding sites in organic and aqueous solvent mixtures.

Distribution map of gadolinium deposition within the cerebellum following GBCA administration.

Gadolinium-based contrast agents (GBCAs) are an essential tool in clinical MRI. Millions of doses are administered annually to patients worldwide.1 However, free gadolinium, the basis of GBCAs, is extremely toxic in only small amounts. Gadolinium has an atomic radius similar to that of calcium and can interfere with calcium-dependent processes such as voltage-gated calcium channels or calcium-activated enzymes.1 To reduce toxicity, GBCAs are composed of gadolinium in chelated form. Following GBCA administration, presumably the gadolinium–chelate complex is excreted intact by the kidneys in patients with normal renal function. Each of the 9 Food and Drug Administration–approved MRI contrast agents has its own specific chelate, leading to variation in stabilities of the gadolinium–chelate complex. GBCAs are generally classified as either linear or macrocyclic based on chelate structure. An ionic, macrocyclic structure has the highest kinetic and thermodynamic stabilities.1

Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

Antarlides F-H, new members of the antarlide family produced by Streptomyces sp. BB47.

Castration-resistant prostate cancer (CRPC) is the most aggressive form of this disease. CRPC remains dependent on androgen receptor (AR) signaling. Therefore, a novel AR antagonist, enzalutamide, is used clinically for the treatment of men with metastatic CRPC. However, enzalutamide-resistant AR has appeared, and a new type of AR antagonist is desired. Previously, in the course of screening for a new type of AR antagonist, we isolated a series of compounds, designated antarlides A-E, that share a novel 22-membered-ring macrocyclic structure and are produced by Streptomyces sp. BB47. In the present study, we found that this strain also produces antarlides F-H as minor components. Antarlide F is a novel geometric isomer of known antarlides. On the other hand, antarlides G and H are new members of the antarlide family that have a 20-membered-ring macrocyclic structure. Antarlides G and H inhibited the binding of androgen to AR in vitro at concentrations similar to those observed with antarlides A-E. In addition, antarlide G inhibited the transcriptional activity of not only wild-type AR but also enzalutamide-resistant AR, suggesting that antarlides with either 22- or 20-membered rings may serve as potent third-generation AR antagonists capable of overcoming resistance to enzalutamide.

Mechanistics and photo‐energetics of macrocycles and photodynamic therapy: An overview of aspects to consider for research

Research within the field of photodynamic therapy has escalated over the past 20years. The required conjunctional use of photosensitizers, particularly of the macrocycle structure, has lead to a vast repertoire of derivatives that branch classes and subclasses thereof. Each exhibits a differential range of physiochemical properties that influence their potential applications within the larger phototherapy field for use in either diagnostics, photodynamic therapy, both or none. Herein, we provide an overview of these properties as they relate to photodynamic therapy and to a lesser extent diagnostics. By summarizing the mechanistics of photodynamic therapy coupled to the photo-energetics displayed by macrocycle photosensitizers, we aimed to highlight the critical aspects any researcher should be aware of and consider when selecting and performing research for therapeutic application purposes. These include photosensitizer, photophysical and structural properties, synthesis design and subsequent attributes, main applications within research, common shortcomings exhibited and the current methods practiced to overcome them.

Natural Occurrence, Synthesis and Biological Applications of Spermidine Alkaloids

Spermidine alkaloids are polyaminated macrocycles containing a lactam ring, which are biosynthetically derived from L-Orn or L-Arg via putrescine intermediates. The presence of these polyamines in nature is very limited, occurring in only a few plant families, and therefore the isolation of spermidine alkaloids serves chemotaxonomic purposes. The interest in the isolation and synthesis of these alkaloids also results from the structural complexity and broad range of bioactivity attributed to these macrocyclic structures. Keywords: Spermidine alkaloids, natural occurrence, synthesis, bioactivity, applications, structural diversity.

Redox reactions of [Ru(NH3)6]2 +/3 +, [Fe(CN)6]3 −/4 − and Fe2 +/3 + on pristine and electrochemically modified carbon nanowalls under physical adsorption of compounds with the skeletal and macrocyclic structure

For pristine (P-CNWs) and functionalized (F-CNWs) carbon nanowalls (CNWs), the effect of physical adsorption of certain compounds with the skeletal structure of bicyclic molecules (camphor, borneol) and also of macrocyclic compounds (Na+ complexes of cryptand 222 (cryptate) and cucurbit [7]uryl) on the kinetic parameters of redox reactions ([Ru(NH3)6]2+/3+, [Fe(CN)6]3−/4− and Fe2+/3+) has been studied systematically for the first time by the methods of cyclic voltammetry. It is shown, that the adsorption of these compounds on F-CNWs does not change the rate constants k0 of [Ru(NH3)6]2+/3+ and [Fe(CN)6]3−/4− redox reactions, whereas their adsorption on P-CNWs leads to a decrease in k0 by the factor 2.5–10. For the Fe2+/3+ reaction at the presence of organic compounds under study, the effect of inhibition is observed for P-CNWs and for F-CNWs, though to the lesser extent. The diametrically opposite effects of the adsorption of camphor and borneol on the kinetics of this reaction are observed with the transition from the pristine to functionalized electrode surface. It is shown, that the adsorption of two-dimensional condensed layers of camphor and borneol on the atomically smooth mercury surface, induces a decrease in k0 for [Ru(NH3)6]2+/3+ reaction, substantially more pronounced, as compared to P-CNWs (by the factor of 25 and 40, respectively). This difference can be explained by the peculiarities of the topology of carbon nanowalls which determines the preferential occurrence of the redox reactions on the edges of basal planes where the formation of condensed layers by the skeletal and macrocyclic molecules seems to be complicated.

The Performance of Several Docking Programs at Reproducing Protein-Macrolide-Like Crystal Structures.

The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

A Porphyrin MOF and Ionic Liquid Biocompatible Matrix for the Direct Electrochemistry and Electrocatalysis of Cytochrome c

A porphyrin metal-organic framework CoTCPP with large surface area and the macrocyclic conjugated structures was constructed from [5,10,15,20- (4-carboxyphenyl)porphyrin]Co(III) and characterized. Furthermore, an electrochemical platform based on CoTCPP and ionic liquid (IL) immobilizing cytochrome c (Cyt c) was studied by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and amperometric current-time curve. The results of electrochemical and spectroscopic measurements showed that Cyt c remained bioactivity and achieved fast electron transfer on the IL/CoTCPP composite film modified electrode. The proposed modified electrode displayed linear response to NO2− in the range of 3.5–2800 μM, with a lower detection limit (1.1 μM) and smaller apparent Michaelis-Menten constant KM (0.28 mM). Thus, the IL/CoTCPP composite film could be applied as a biocompatible platform for the direct electrochemistry and electrocatalysis for NO2−of Cyt c.

P3.02a-009 TPX-0005: A Multi-Faceted Approach to Overcoming Clinical Resistances from Current ALK or ROS1 Inhibitor Treatment in Lung Cancer: Topic: ALK Biomarkers

ALK and ROS1 kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients. However, the emergence of drug resistance limits their long term clinical applications. The mechanisms of resistance often include gene amplification, acquired mutations, bypass signaling, and epithelial-mesenchymal transition (EMT). The bypass and EMT-based resistances constitute the majority of the resistant patient population, especially after multiple kinase inhibitor treatment. None of the current ALK or ROS1 inhibitors can overcome bypass or EMT-based resistance when applied as a single agent therapy. SRC kinase has been identified to contribute broadly to cancer treatment resistance via participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangement, migration, adhesion, invasion, motility, and survival. SRC/FAK signaling plays important roles in regulating antitumor immunity, cancer stem-like properties, and EMT. Here we deployed a polypharmacology approach to combatting multiple resistance mechanisms spontaneously. Recombined enzyme assays, engineered cell lines and H2228 cells were used to evaluate TPX-0005 in in vitro and in vivo models. TPX-0005 is a potent ALK/ROS1/TRK inhibitor with a rigid three-dimensional macrocyclic structure and a much smaller size (MW <370) than current ALK/ROS1/TRK inhibitors. The compact structure allows TPX-0005 efficiently target the center of ATP binding site and be able to circumvent the steric interference from clinical resistant mutations. Therefore, TPX-0005 potently inhibited both wild type and mutant ALK/ROS1/TRK fusion proteins including gatekeeper and solvent front mutations at low nanomolar concentration. In addition to its primary targets, TPX-0005 is also a potent SRC/FAK inhibitor. H2228 lung cancer cell line, endogenously expressing EML4-ALKv3 protein, is refractory to crizotinib and ceritinib in cell proliferation assay (IC50 ∼1 μM). The upregulation of multiple RTKs including EGFR and IGFR, as well as cancer stem cell marker CD44 in H2228 cells is believed to confer the primary resistance to selective ALK inhibitors. Inhibition of SRC/FAK kinases will modulate RTK expression and cancer stem-like properties to restore the sensitivity to ALK inhibitor. TPX-0005 inhibited the phosphorylation of EML4-ALK (IC50 13 nM), SRC and FAK (IC50s 70-80 nM), along with other downstream signaling targets in H2228 cells, leading to dose-dependent down-regulation of EGFR and CD44 expression levels. As a result, TPX-0005 overcame the primary resistance and effectively inhibited cell proliferation (IC50 ∼0.1 μM) and cell migration of H2228 cells. TPX-0005 exerts unprecedented polypharmacology profile for combatting multiple resistance mechanisms including acquired mutations, bypass signaling, cancer stemness, and metastasis, that warrants further clinical investigation.

Rhodium(I) macrocyclic and cage-like structures containing diphosphine bridging ligands

Three series of rhodium organometallic complexes, mono-(1c, 2c, 5c, 6c), di-(1a-6a) and tetranuclear (1b, 5b, 6b), containing six different diphosphines 1,1′-bis(diphenylphosphino)methane or dppm (1), 1,2-bis(diphenylphosphino)ethane or dppe (2), 1,4-bis(diphenylphosphino)butane or dppb (3), bis(diphenylphosphino)acetylene or dppa (4), 1,2-bis(diphenylphosphino)benzene or dppbz (5) and 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene or xantphos (6) were successfully synthesised. These Rh(I) complexes were characterised by conventional techniques. The influence of the flexibility/rigidity of these P-donor ligands was carefully analysed, including their effect on both synthesis and catalysis. The luminescent properties of the dinuclear and tetranuclear complexes were investigated, and only those containing dppa, dppbz and xantphos displayed luminescence. Structures of the dinuclear complexes were modelled by using DFT methods in order to elucidate the most reasonable conformation. The different types of complexes were applied in the catalytic hydrogenation of (E)-4-phenylbut-3-en-2-one, showing high activity and similar catalytic behaviour. No cooperative effect could be inferred. Three series of 1D, 2D and 3D rhodium complexes were successfully synthesised, and their emission properties were analysed. The large number of isomeric forms of the 2D were analysed by DFT methods. Their use in catalytic hydrogenation of (E)-4-phenylbut-3-en-2-one was studied showing high selectivity towards the formation of 4-phenylbutan-2-one.

Synthesis, Characterisation and Crystal Structure of a Novel Pyridyl Urea Macrocycle

A novel pyridyl urea based macrocycle has been synthesised and fully characterised including a single crystal X-ray structure determination. The synthetic approach first involves the reaction of benzyloxycarbonylaminopropyl-3-isocyanate with t-butyl 2-[(2-aminopyridin-3-yl)oxy]acetate resulting in a coupling product. After deprotection of the amine and acid moieties and coupling subsequent coupling in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a macrocycle is formed. The structures of the compounds were confirmed by mass spectrometry and NMR spectroscopy. The X-ray crystal structure of the macrocycle reveals as expected a non-binding conformation with an intramolecular hydrogen bond between the urea NH and the pyridyl nitrogen.

The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies.

Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron-magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the β-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.

Controlled release from cucurbituril

The unique pumpkin-shape macrocyclic structure with inherent cavities renders cucurbituril (CB) a type of versatile supramolecular container. On account of their good biocompatibility and low toxicity, the applications of CB to encapsulate drug molecules provide promising candidates and the pharmacological activities have been investigated currently. How to control over the uptake and release of the guest at will is significant for practical applications of drug delivery. The noncovalent nature of supramolecular interactions offers variety of options to control the release of guest molecules from CB under external stimuli, including pH, temperature, metal cations, competing guests, light, redox and so on. Moreover, CB containers are capable of assembling into higher ordered supramolecular structures such as polymers, nanoparticles, hydrogels, and colloids, which greatly enrich the scope of CB-type inclusion materials. Those results provide useful principles and guidelines for controlled release from supramolecular containers.

Variation of the Molecular Conformation, Shape, and Cavity Size in Dinuclear Metalla-Macrocycles Containing Hetero-Ditopic Dithiocarbamate-Carboxylate Ligands from a Homologous Series of N-Substituted Amino Acids.

A homologous series of dithiocarbamate ligands derived from N-substituted amino acids was reacted with different diorganotin dichlorides to give 18 diorganotin complexes. Spectroscopic and mass spectrometric analysis evidenced the formation of assemblies with six-coordinate tin atoms embedded in skewed-trapezoidal bipyramidal coordination environments of composition C2SnS2O2. Single-crystal X-ray diffraction analysis for three of the compounds revealed a one-dimensional polymeric structure for the complex with the ligand derived from 5-aminopentanoic acid, which through further intermolecular Sn···O interactions generated an overall two-dimensional coordination polymer containing 40-membered hexanuclear tin macrocycles. On the contrary, the ligands derived from 6-aminohexanoic and 8-aminooctanoic acid provided the expected 22- and 26-membered dinuclear macrocyclic structures. Density functional theory calculations for a representative series of macrocyclic complexes of composition [Me2SnLx]2 with Lx = ¯S2CN(Me)-(CH2)x-COO¯ (x = 3-12) enabled a detailed analysis of the variations in the molecular conformation, shape, and cavity size of the macrocycles in dependence of the aliphatic spacer. Because of odd-even effects, the difunctional ligands can adopt either a curved or a twisted-pincer shape, while the SnSxO4-x (x = 0-4) moieties can act either as linear or angular tectons with varying connectivity angles.

Synthesis of Heterocycle‐Bridged Peptidic Macrocycles through 1,3‐Diyne Transformations

Macrocyclic tetrapeptide analogues containing a 1,3‐diyne moiety were synthesized by a Glaser–Hay‐type macrocyclization. The obtained 1,3‐diyne was evaluated as a handle to introduce heterocycles into the macrocyclic structure. It was shown that the macrocyclic 1,3‐diynes were successfully transformed into various heterocycles by nucleophilic attack of (bis)nucleophiles to the diyne moiety. Treatment with NaHS or H2O as nucleophiles gave rise to 2,5‐bridged thiophenes or furans, whereas the use of hydrazines and hydroxylamine gave rise to the corresponding pyrazole‐ and isoxazole‐containing macrocycles. In addition, a thermoreversible Diels–Alder cycloaddition of a cyclopeptidic bridged furan was demonstrated.

Improving the Binding Affinity of in-Vitro-Evolved Cyclic Peptides by Inserting Atoms into the Macrocycle Backbone.

Cyclic peptides binding to targets of interest can be generated efficiently with powerful in vitro display techniques, such as phage display or mRNA display. The cyclic peptide libraries screened with these methods are generated by altering in a combinatorial fashion the amino acid sequence of the peptides, the number of amino acids in the macrocycle rings, and the cyclization chemistry. A structural element that cannot easily be varied in the cyclic peptides is the backbone, which is built from amino acids, each of which contributes three atoms to the macrocyclic ring structure. Here, we proposed to improve the affinity of a phage-selected bicyclic peptide inhibitor of coagulation factor XII (FXII) by screening variants with one or two carbon atoms inserted into different positions of the backbone, and thus tapping into a structural space that was not sampled by phage display. Two mutants showed 4.7- and 2.5-fold improved Ki values. The better one blocked FXII with a Ki of 1.5±0.1 nm and inhibited activation of the intrinsic coagulation pathway (EC2x 1.7 μm). The strategy of ring size variation by one or several atoms should be generally applicable for the affinity maturation of in-vitro-evolved cyclic peptides.

Theoretical prediction of some novel nanotubes composed of macrocyclic structures: A DFT study

Our interests in this paper are the elucidation of structural and electronic properties of some π-conjugated macrocycles composed of borazine and alumazene rings as well as the investigation of their potential utility for the creation of new nanotubes. Here, the calculations are performed at B3LYP/6-31+G(d) and M06-2X/6-31+G(d)//B3LYP/6-31+G(d) levels of theory. The results suggest that the self-assembly of the macrocyclic compounds can be considered to form new nanotubes through π-π stacking. Also, meaningful correlations are found between the stability and photoconductivity applications of the nanotubes and the number of stacked π-conjugated macrocycles.