Synthesis, structures, and cytotoxicity insights of organotin(IV) complexes with thiazole-appended pincer ligand.

Diorganotin complexes of the compositions [Me2Sn(L)] (1), [n-Bu2Sn(L)] (2), [Ph2Sn(L)]⋅C6H6 (3), [Bz2Sn(L)]⋅C6H6 (4) and [n-Oct2Sn(L)] (5) were synthesized by reacting R2SnO (R = Me, n-Bu, Ph, Bz or n-Oct) with the N2,N6-di(thiazol-2-yl)pyridine-2,6-dicarboxamide (H2L, where H2 denotes the two acidic protons) in refluxing toluene. Additionally, the mono-n-butyltin complex [n-BuSn(HL)Cl2]·H2O (6) was synthesized from n-BuSnCl3 and H2L in acetonitrile. Compounds were characterized by FT-IR, 1H, 13C and 119Sn NMR spectroscopy, while their solid-state structures were examined using single-crystal X-ray diffraction studies. In diorganotin compounds 1-5, the dianionic tridentate ligands (Npy, N-, N-) act as κ-N3 chelators. In 6, the L moiety (O, Npy, N-) acts as a κ-ON2 tridentate chelator, with involvement of one of the carboxamide oxygen atoms. The coordination polyhedron around the Sn(IV) ion is completed either by two axial Sn-R ligands in compounds 1-5 or by n-Bu and Cl ligands in compound 6, giving rise to distorted trigonal bipyramid or octahedral structures, respectively. The tin NMR results show that the penta-coordinated structures of compounds 1-5 and the hexacoordinated structure of compound 6, observed in the solid-state, are retained in solution. The in vitro antitumor activities of 1-5 were tested on T-47D breast cancer cells. Of these, diphenyltin compound 3 showed the highest anti-proliferative effect, with an IC50 of 10 ± 1.60 µM. Compound 3 exhibited selective toxicity, potentially inducing apoptosis via reactive oxygen species generation and nuclear changes, indicating promise as a breast cancer treatment. This study is the first to explore thiazole-appended organotin compounds for cytotoxicity.

Extended shortwave infrared absorbing antiaromatic fluorenium-indolizine chromophores.

Shortwave infrared (SWIR, 1000-1700 nm) and extended SWIR (ESWIR, 1700-2700 nm) absorbing materials are valuable for applications including fluorescence based biological imaging, photodetectors, and light emitting diodes. Currently, ESWIR absorbing materials are largely dominated by inorganic semiconductors which are often costly both in raw materials and manufacturing processes used to produce them. The development of ESWIR absorbing organic molecules is thus of interest due to the tunability, solution processability, and low cost of organic materials compared to their inorganic counterparts. Herein, through the combination of heterocyclic indolizine donors and an antiaromatic fluorene core, a series of organic chromophores with absorption maxima ranging from 1470-2088 nm (0.84-0.59 eV) and absorption onsets ranging from 1693-2596 nm (0.73-0.48 eV) are designed and synthesized. The photophysical and electrochemical properties of these chromophores, referred to as FluIndz herein, are described via absorption spectroscopy in 17 solvents, cyclic voltammetry, solution photostability, and transient absorption spectroscopy. Molecular orbital energies, predicted electronic transitions, and antiaromaticity are compared to higher energy absorbing chromophores using density functional theory. The presence of thermally accessible diradical states is demonstrated using density functional theory and EPR spectroscopy, while XRD crystallography confirms structural connectivity and existence as a single molecule. Overall, the FluIndz chromophore scaffold exhibits a rational means to access organic chromophores with extremely narrow optical gaps.

Carbon-phosphorus stapled Au(I) anticancer agents via bisphosphine induced reductive elimination.

Towards the goal of generating new stabilized gold complexes as potent anticancer agents, we report here a novel class of Au(I) agents from Au(III)-mediated Caryl-P bond formation captured within the same complex by reacting a C^N cyclometalated Au(III) complex with bisphosphines. Cyclometalated Au(III) complexes of the type [Au(C^N)Cl2], where C^N represent different aryl pyridine framework reacted with bis(2-diphenylphosphino)phenyl ether in refluxing methanol to access an unsymmetrical gold complex featuring C-P coupling and Au(I)-phosphine. The complexes were characterized by 1H-NMR, 13C-NMR, and 31P-NMR and mass spectrometry. The structures of the complexes were characterized by X-ray crystallography and purity ascertained by HPLC and elemental analysis. The complexes demonstrate promising anticancer activity in a broad panel of cancer cell lines of different tumor origin. Mechanistically, the complexes induce apoptosis, generate mitochondrial ROS, depolarize mitochondrial membrane potential and modulate mitochondrial respiration in cancer cells. Overall, we developed a new structural class of Au(I) complexes with promising anticancer potential with potential utility in other applications.

Crystal structure of tris-{N,N-diethyl-N'-[(4-nitro-phen-yl)(oxo)meth-yl]carbamimido-thio-ato}cobalt(III).

The synthesis, crystal structure, and a Hirshfeld surface analysis of tris-{N,N-diethyl-N'-[(4-nitro-phen-yl)(oxo)meth-yl]carbamimido-thio-ato}cobalt(III) conducted at 180 K are presented. The complex consists of three N,N-diethyl-N'-[(4-nitro-benzene)(oxo)meth-yl]carbamimido-thio-ato ligands, threefold sym-metric-ally bonded about the CoIII ion, in approximately octa-hedral coordination, which generates a triple of individually near planar metallacyclic (Co-S-C-N-C-O) rings. The overall geometry of the complex is determined by the mutual orientation of each metallacycle about the crystallographically imposed threefold axis [dihedral angles = 81.70 (2)°] and by the dihedral angles between the various planar groups within each asymmetric unit [metallacycle to benzene ring = 13.83 (7)°; benzene ring to nitro group = 17.494 (8)°]. The complexes stack in anti-parallel columns about the axis of the space group (P), generating solvent-accessible channels along [001]. These channels contain ill-defined, multiply disordered, partial-occupancy solvent. Atom-atom contacts in the crystal packing predominantly (∼96%) involve hydrogen, the most abundant types being H⋯H (36.6%), H⋯O (31.0%), H⋯C (19.2%), H⋯N (4.8%), and H⋯S (4.4%).

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

Revealing the Singlet Fission Mechanism for a Silane-Bridged Thienotetracene Dimer.

Tetraceno[2,3-b]thiophene is regarded as a strong candidate for singlet fission-based solar cell applications due to its mixed characteristics of tetracene and pentacene that balance exothermicity and triplet energy. An electronically weakly coupled tetraceno[2,3-b]thiophene dimer (Et2Si(TIPSTT)2) with a single silicon atom bridge has been synthesized, providing a new platform to investigate the singlet fission mechanism involving the two acene chromophores. We study the excited state dynamics of Et2Si(TIPSTT)2 by monitoring the evolution of multiexciton coupled triplet states, 1TT to 5TT to 3TT to T1 + S0, upon photoexcitation with transient absorption, temperature-dependent transient absorption, and transient/pulsed electron paramagnetic resonance spectroscopies. We find that the photoexcited singlet lifetime is 107 ps, with 90% evolving to form the TT state, and the complicated evolution between the multiexciton states is unraveled, which can be an important reference for future efforts toward tetraceno[2,3-b]thiophene-based singlet fission solar cells.

Crystal structures of two formamidinium hexa-fluorido-phosphate salts, one with batch-dependent disorder.

Syntheses of the acyclic amidinium salts, morpholino-formamidinium hexa-fluorido-phosphate [OC4H8N-CH=NH2]PF6 or C5H11N2O+·PF6 -, 1, and pyrrolidinoformamidinium hexa-fluorido-phosphate [C4H8N-CH= NH2]PF6 or C5H11N2 +·PF6 -, 2, were carried out by heating either morpholine or pyrrolidine with triethyl orthoformate and ammonium hexa-fluorido-phosphate. Crystals of 1 obtained directly from the reaction mixture contain one cation and one anion in the asymmetric unit. The structure involves cations linked in chains parallel to the b axis by N-H⋯O hydrogen bonds in space group Pbca, with glide-related chains pointing in opposite directions. Crystals of 1 obtained by recrystallization from ethanol, however, showed a similar unit cell and the same basic structure, but unexpectedly, there was positional disorder [occupancy ratio 0.639 (4):0.361 (4)] in one of the cation chains, which lowered the crystal symmetry to the non-centrosymmetric space group Pca21, with two cations and anions in the asymmetric unit. In the pyrrolidino compound, 2, cations and anions are ordered and are stacked separately, with zigzag N-H⋯F hydrogen-bonding between stacks, forming ribbons parallel to (101), extended along the b-axis direction. Slight differences in the delocalized C=N distances between the two cations may reflect the inductive effect of the oxygen atom in the morpholino compound.

A Peptoid-like Approach Led to Lactam-Lactam Dimer Formation in 2-Hydroxy-N-alkyl-N-phenyl-nicotinamides and Their Polymorphism and Solvatomorphism.

Four 2-hydroxy-N-alkyl-N-phenyl-nicotinamides (1-4) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of N-phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound 1, and one anhydrous form and one hydrate were obtained for compound 2. Polymorphism was observed in compounds 3 and 4. The molecules were found to be in the keto form rather than the enol tautomer. Because of steric effects, the molecules took on an E configuration, leading to a hairpin-like geometry. A lactam-lactam dimer synthon was formed in all solvent-free structures, and a tetramer motif was observed for the first time. Dehydration of the two hydrates of 1 and the hydrate of 2 led to their respective solvent-free form. Phase transition between the polymorphs was revealed in compound 3. Theoretical calculations, including conformational energy evaluation, hydrate forming propensity assessment, and lattice energy appraisal, were performed to provide a reasonable explanation for the keto tautomer and the formation of the hydrates of compound 1.

Circumventing Physicochemical Barriers of Cyclometalated Gold(III) Dithiocarbamate Complexes with Protein-Based Nanoparticle Delivery to Enhance Anticancer Activity.

Optimizing the bioavailability of drug candidates is crucial to successful drug development campaigns, especially for metal-derived chemotherapeutic agents. Nanoparticle delivery strategies can be deployed to overcome physicochemical limitations associated with drugs to improve bioavailability, pharmacokinetics, efficacy, and minimize toxicity. Biodegradable albumin nanoconstructs offer pragmatic solutions for drug delivery of metallodrugs with translational benefits in the clinic. In this work, we explored a logical approach to investigate and resolve the physicochemical drawbacks of gold(III) complexes with albumin nanoparticle delivery to improve solubility, enhance intracellular accumulation, circumvent premature deactivation, and enhance anticancer activity. We synthesized and characterized stable gold(III) dithiocarbamate complexes with a variable degree of cyclometalation such as phenylpyridine (C^N) or biphenyl (C^C) Au(III) framework and different alkyl chain lengths. We noted that extended alkyl chain lengths impaired the solubility of these complexes in biological media, thus adversely impacting potency. Encapsulation of these complexes in bovine serum albumin (BSA) reversed solubility limitations and improved cancer cytotoxicity by ∼25-fold. Further speciation and mechanism of action studies demonstrate the stability of the compounds and alteration of mitochondria bioenergetics, respectively. We postulate that this nanodelivery strategy is a relevant approach for translational small-molecule gold drug delivery.

Foreword to the special virtual issue on Modern approaches and tools for teaching crystallography.

A compilation of articles with a strong teaching element published since 2018 is presented alongside an overview of the articles in the special issue on this topic.

Crystal structure studies and Hirshfeld surface analysis of 4-(di-methyl-aza-nium-yl)-2-hy-droxy-anilinium dichloride monohydrate at 90†K.

The crystal structure and a Hirshfeld surface analysis of the substituted anilinium salt 4-(di-methyl-aza-nium-yl)-2-hy-droxy-anilinium dichloride monohydrate, C8H14N2O+·2Cl-·H2O, at low temperature (90 K) are presented. The organic cation is essentially planar: the r.m.s. deviation of its non-hydrogen atoms (aside from the two methyl groups) is 0.0045 Å. The methyl carbons are 1.3125 (12) Šand 1.1278 (12) Šeither side of the mean plane. The crystal packing involves extensive hydrogen bonding of types O-H⋯Cl, N-H⋯Cl, N-H⋯OW, and OW-HW⋯Cl (where W = water), which arrange into chains of R 2 4(12) motifs that combine to form corrugated layers parallel to (10). Atom-atom contacts for the cation primarily involve hydrogen, leading to the most abundant coverage percentages being 51.3% (H⋯H), 23.0% (H⋯Cl), 12.9% (H⋯O), and 9.7% (C⋯H).

Crystal structures of four organic salts of trihexyphenidyl at 90†K.

The syntheses and crystal structure studies of four organic salts of trihexyphenidyl, viz., trihexyphenidylium [1-(3-cyclo-hexyl-3-hy-droxy-3-phenyl-prop-yl)piperidin-1-ium] 4-nitro-benzoate, C20H32NO+·C7H4NO4 - (I), trihexyphenidylium 4-hy-droxy-benzoate, C20H32NO+·C7H5O- (II), trihexyphenidylium 4-bromo-benzoate, C20H32NO+·C7H4BrO2 - (III), and trihexyphenidylium thio-phene-2-carboxyl-ate hemihydrate, 2C20H32NO+·2C5H3O2S-·H2O (IV), con-ducted at 90 K are described. Structures I, II, and III are solvent free with one cation-anion pair per asymmetric unit, while IV crystallizes as a hemihydrate, having two cation-anion pairs and one water of crystallization in its asymmetric unit. Structures I and III exhibit configurational disorder of the cation. Structure IV also exhibits disorder, but only of the thio-phene-2-carboxyl-ate anions. Structure II is a non-merohedric twin by a twofold rotation about [403]. The main supra-molecular motifs in I, II, and III are similar R 2 2(10) rings between cation-anion pairs, although their packing within the crystals is distinct. As a consequence of having two cation-anion pairs and a water mol-ecule in its asymmetric unit, the packing in IV is by far the most complex of the four structures, its hydrogen-bonding patterns being quite different from I, II, or III. In all the crystals studied, N-H⋯O, O-H⋯O, and C-H⋯O inter-actions are observed, plus C-H⋯Br close contacts for III.

The synthesis, crystal structure and spectroscopic analysis of (E)-3-(4-chloro-phen-yl)-1-(2,3-di-hydro-benzo[b][1,4]dioxin-6-yl)prop-2-en-1-one.

The synthesis, crystal structure and spectroscopic analysis of (E)-1-(2,3-di-hydro-benzo[b][1,4]dioxin-6-yl)-3-(4-chloro-phen-yl)prop-2-en-1-one (C17H13ClO3), a substituted chalcone, are described. The overall geometry of the mol-ecule is largely planar (r.m.s. deviation = 0.1742 Å), but slightly kinked, leading to a dihedral angle between the planes of the benzene rings at either side of the mol-ecule of 8.31 (9)°. In the crystal, only weak inter-actions determine the packing motifs. These include C-H⋯O and C-H⋯Cl hydrogen bonds and π-π overlap of aromatic rings.

Crystal structure and Hirshfeld-surface analysis of a monoclinic polymorph of 2-amino-5-chloro-benzo-phenone oxime at 90†K.

The synthesis and crystal structure of a monoclinic polymorph of 2-amino-5-chloro-benzo-phenone oxime, C13H11ClN2O, are presented. The mol-ecular conformation results from twisting of the phenyl and 2-amino-5-chloro benzene rings attached to the oxime group, which subtend a dihedral angle of 80.53 (4)°. In the crystal, centrosymmetric dimers are formed as a result of pairs of strong O-H⋯N hydrogen bonds. A comparison is made to a previously known triclinic polymorph, including differences in atom-atom contacts obtained via a Hirshfeld-surface analysis.

Preparation of a Rigid and Nearly Coplanar Bis-tetracene Dimer through an Application of the CANAL Reaction.

A rigid tetracene dimer with a substantial interchromophore distance has been prepared through an application of the recently developed catalytic arene-norbornene annulation (CANAL) reaction. An iterative cycloaddition route was found to be unsuccessful, so a shorter route was adopted whereby fragments were coupled in the penultimate step to form a 13:1 mixture of two diastereomers, the major of which was isolated and crystallized. Constituent tetracene moieties are linked with a rigid, well-defined bridge and feature a near-co-planar mutual orientation of the acenes.

An anti-glioblastoma gold(i)-NHC complex distorts mitochondrial morphology and bioenergetics to induce tumor growth inhibition.

Glioblastoma multiforme (GBM) is the most lethal brain cancer subtype, often advanced by the time of initial diagnosis. Existing treatment modalities including surgery, chemotherapy and radiation have been stymied by recurrence, metastasis, drug resistance and brain targetability. Here, we report a geometrically distinct Au(i) complex ligated by N^N-bidentate ligands and supported by a N-heterocyclic ligand that modulates mitochondrial morphology to inhibit GBM in vitro and in vivo. This work benefits from the facile preparation of anti-GBM Au(i)-NHC complexes.

A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells.

Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and have been leveraged for biological use. In this work, we report the synthesis and characterization of a novel class of cyclometalated [C^N] Au(III) complexes bearing secondary diamines including a norbornane backbone, (2R,3S)-N2,N3-dibenzylbicyclo[2.2.1]heptane-2,3-diamine, or a cyclohexane backbone, (1R,2R)-N1,N2-dibenzylcyclohexane-1,2-diamine. X-ray crystallography confirms the square-planar geometry and chirality at nitrogen. The electronic character of the conformationally restricted norbornane backbone influences the electrochemical behavior with redox potentials of -0.8 to -1.1 V, atypical for Au(III) complexes. These compounds demonstrate promising anticancer activity, particularly, complex 1, which bears a benzylpyridine organogold framework, and supported by the bicyclic conformationally restricted diaminonorbornane, shows good potency in A2780 cells. We further show that a cellular response to 1 evokes reactive oxygen species (ROS) production and does not induce mitochondrial dysfunction. This class of complexes provides significant stability and reactivity for different applications in protein modification, catalysis, and therapeutics.

Hydrogen-Bonding Trends in a Bithiophene with 3- and/or 4-Pyridyl Substituents.

To improve the charge-carrier transport capabilities of thin-film organic materials, the intermolecular electronic couplings in the material should be maximized. Decreasing intermolecular distance while maintaining proper orbital overlap in highly conjugated aromatic molecules has so far been a successful way to increase electronic coupling. We attempted to decrease the intermolecular distance in this study by synthesizing cocrystals of simple benzoic acid coformers and dipyridyl-2,2'-bithiophene molecules to understand how the coformer identity and pyridine N atom placement affected solid-state properties. We found that with the 5-(3-pyridyl)-5'-(4-pyridyl)-isomer, the 4-pyridyl ring interacted with electrophiles and protons more strongly. Synthesized cocrystal powders were found to have reduced average crystallite size in reference to the parent compounds. The opposite was found for the intermolecular electronic couplings, as determined via density functional theory (DFT) calculations, which were relatively large in some of the cocrystals.

Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction.

While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4'-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

Solvatomorphism and first-time observation of acid-acid catemer in 4-phenylamino-benzoic acids.

To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (1-8) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds 1, 3 and 8, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for 2, which has a rarely observed acid-acid catemer motif. Two of the solvates (1-S and 8-S) have pyridine in the lattice while the other (3-S) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.