Coordination‐Driven Self‐Assembly and Anticancer Potency Studies of Ruthenium–Cobalt‐Based Heterometallic Rectangles

Three new cobalt–ruthenium heterometallic molecular rectangles, 1 – 3 , were synthesized through the coordination‐driven self‐assembly of a new cobalt sandwich donor, (η⁵‐Cp)Co[C₄‐trans‐Ph₂(4‐Py)₂] (L ; Cp: cyclopentyl; Py: pyridine), and one of three dinuclear precursors, [(p‐cymene)₂Ru₂(OO∩OO)₂Cl₂] [OO∩OO: oxalato ( A₁ ), 5,8‐dioxido‐1,4‐naphthoquinone ( A₂ ), or 6,11‐dioxido‐5,12‐naphthacenedione ( A₃ )]. All of the self‐assembled architectures were isolated in very good yield (92–94 %) and were fully characterized by spectroscopic analysis; the molecular structures of 2 and 3 were determined by single‐crystal X‐ray diffraction analysis. The anticancer activities of bimetallic rectangles 1 – 3 were evaluated with a 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) assay, an autophagy assay, and Western blotting. Rectangles 1 – 3 showed higher cytotoxicity than doxorubicin in AGS human gastric carcinoma cells. In addition, the autophagic activities and apoptotic cell death ratios were increased in AGS cells by treatment with 1 – 3 ; the rectangles induced autophagosome formation by promoting LC3‐I to LC3‐II conversion and apoptotic cell death by increasing caspase‐3/7 activity. Our results suggest that rectangles 1 – 3 induce gastric cancer cell death by modulating autophagy and apoptosis and that they have potential use as agents for the treatment of human gastric cancer.     

Self‐Assembled Hexanuclear Organometallic Cages: Synthesis,Characterization, and Host–Guest Properties

A series of iridium‐ and rhodium‐based hexanuclear organometallic cages containing 2,5‐dichloro‐3,6‐dihydroxy‐1,4‐benzoquinone, 9,10‐dihydroxy‐1,4‐anthraquinone, and 6,11‐dihydroxynaphthacene‐5,12‐dione ligands were synthesized from the self‐assembly of the corresponding molecular “clips” and 2,4,6‐tri(4‐pyridyl)‐1,3,5‐triazine ligands in good yields. These organometallic cages can form inclusion systems with a wide variety of π‐donor substrates, including coronene, pyrene, [Pt(acac)₂], and hexamethoxytriphenylene. The 1:1 complexation of the resulting supramolecular assemblies was confirmed by ¹H NMR spectroscopy. Large complexation shifts (Δδ>1 ppm) were observed in the ¹H NMR spectra of guests in the presence of cage [Cp*₆M₆(μ‐DHNA)₃(tpt)₂](OTf)₆ ( 6a ; M=Ir, tpt=2,4,6‐tri(4‐pyridyl)‐1,3,5‐triazine). The formation of discrete 1:1 donor–acceptor complexes, pyrene ?6 b (M=Rh), coronene ?6 a , coronene ?6 b , and [Pt(acac)₂] ?6 a was confirmed by their single‐crystal X‐ray analyses. In these systems, the most important driving force for the formation of guest–host complexes is clearly the donor–acceptor π???π stacking interaction, including charge‐transfer interactions between the electron‐donating and electron‐accepting aromatic components. These structures provide compelling evidence for the existence of strong attractive forces between the electron‐deficient triazine core and electron‐rich guest. The results presented here may provide useful guidance for designing artificial receptors for functional biomolecules.     

[2+2] Photocycloaddition of 2‐Morpholinoprop‐2‐enenitrile to Perinaphthenone

Perinaphthenone (=1H‐phenalen‐1‐one), known for efficient population of its T₁ (π,π*) state and suggested as a standard sensitizer for singlet oxygen (¹Δg) formation, forms a single stereoisomer of a head‐to‐tail [2+2] photoadduct across its C(2)=C(3) bond with 2‐morpholinoprop‐2‐enenitrile in benzene by broad band UV excitation (λ≥280 nm). The reaction is advantageously run to low conversion of starting materials only. The structure of the adduct, especially the relative configuration at C(9), has been derived from ¹H‐NMR data including NOE signal enhancement studies.     

Remarkable Shape‐Sustaining,Load‐Bearing,and Self‐Healing Properties Displayed by a Supramolecular Gel Derived from a Bis‐pyridyl‐bis‐amide of L‐Phenyl Alanine

A series of bis‐amides decorated with pyridyl and phenyl moieties derived from L ‐amino acids having an innocent side chain (L ‐alanine and L ‐phenyl alanine) were synthesized as potential low‐molecular‐weight gelators (LMWGs). Both protic and aprotic solvents were found to be gelled by most of the bis‐amides with moderate to excellent gelation efficiency (minimum gelator concentration=0.32–4.0 wt. % and gel–sol dissociation temperature T_gel=52–110 °C). The gels were characterized by rheology, DSC, SEM, TEM, and temperature‐variable ¹H NMR measurements. pH‐dependent gelation studies revealed that the pyridyl moieties took part in gelation. Structure–property correlation was attempted using single‐crystal X‐ray and powder X‐ray diffraction data. Remarkably, one of the bis‐pyridyl bis‐amide gelators, namely 3,3‐Phe (3‐pyridyl bis‐amide of L ‐phenylalanine) displayed outstanding shape‐sustaining, load‐bearing, and self‐healing properties.     

Head‐to‐Tail Intermolecular Hydrogen Bonding of OH and NH Groups with Fluoride

To explore the anion‐recognition ability of the phenolic hydroxyl group and the amino hydrogen, we synthesized three different acridinedione (ADD) based anion receptors, 1 , 2 and 3 , having OH, NH, and combination of OH and NH groups, respectively. Absorption, emission and ¹H NMR spectral studies revealed that receptor 1 , having only a phenolic OH group, shows selective deprotonation of the hydroxyl proton towards F^?, which results in an “ON–OFF”‐type signal in the fluorescence spectral studies. Receptor 2 , which only has an amino hydrogen, also shows deprotonation of the amino hydrogen with F^?, whereas receptor 3 (having both OH and NH groups) shows head‐to‐tail intermolecular hydrogen bonding of OH and NH groups with F^? prior to deprotonation. The observation of hydrogen bonding of the OH and NH groups in a combined solution of 1 and 2 with F^? in a head‐to‐tail hetero‐intermolecular fashion, and the absence of head‐to‐head and tail‐to‐tail intermolecular hydrogen bonding in 1 and 2 with F^?, prove that the difference in the acidity of the OH and NH protons leads to the formation of an intermolecular hydrogen‐bonding complex with F^? prior to deprotonation. The presence of this hydrogen‐bonding complex was confirmed by absorption spectroscopy, 3D emission contour studies, and ¹H NMR titration.     

Structural Studies of Self‐Folding Cavitands

Resorcinarene‐based cavitands 1a – c fold into a deep open‐ended cavity by means of intramolecular hydrogen bonds in both apolar solutions and the solid state. The X‐ray crystal‐structure analysis of cavitand 1a features a seam of secondary amide C=O⋅⋅⋅H−N interactions that bridge adjacent rings and are held in place by intra‐annular hydrogen bonds. This results in a cavity of 9.2×7.0 Å dimensions. The arrangement of the amides in 1a – 1c is cycloenantiomeric, with clock‐ and counterclockwise orientation of the head‐to‐tail amide sequence. Interconversion rates of the two enantiomers are controlled by solvent polarity: the rate is slow on the NMR time‐scale in aromatic solvents and CDCl₃, but fast in (D₆)acetone. The ¹H‐ and ¹³C‐NMR‐spectral analysis is in agreement with the crystallographic data. Chiral cavitand 1b with eight HN−C(O)−C*HMeEt ((+)‐(S)) groups on its upper rim exists as two cyclodiastereoisomers (in a ca. 3 : 1 ratio) in apolar solution. A `library' of 512 diastereoisomeric cavitands 1c is obtained as a mixture by using the corresponding racemic acid chloride.     

Encapsulation Enhanced Dimerization of a Series of 4‐Aryl‐N‐Methylpyridinium Derivatives in Water: New Building Blocks for Self‐Assembly in Aqueous Media

The construction of supramolecular systems in aqueous media is still a great challenge owing to the limited sources of building blocks. In this study, a series of 4‐aryl‐N‐methylpyridinium derivatives have been synthesized. They formed very stable host–guest (1:2) complexes with CB[8] in water (binding constants up to 10¹⁴ M ^?2) with the two guest molecules arranged in a head‐to‐tail manner and the complexes showed high thermostability, which was revealed by ¹H NMR and UV/Vis spectroscopic studies, ITC, and crystallographic analysis.     

Synthesis,cytotoxicity and anti‐metastatic properties of new pyridyl–thiazole arene ruthenium(II) complexes

A series of novel ruthenium(II)–cymene complexes ( 1 – 8 ) containing substituted pyridyl–thiazole ligands, [Ru(η⁶‐p‐cymene)(L)Cl]Cl (L = N,N‐chelating derivatives), have been synthesized and characterized using elemental analysis, infrared, ¹H NMR and ¹³C NMR spectroscopies and mass spectrometry. All these complexes not only display marked cytotoxicity in vitro against three different human cancer cell lines (HeLa, A549 and MDA‐MB‐231), but also exhibit promising anti‐metastatic activity at sub‐cytotoxic concentrations. Cell cycle analysis shows that the ruthenium(II) complex‐induced growth inhibition was mainly caused by S‐phase cell cycle arrest. Further protein level analysis suggests that compound 5 may exert antitumor activity via a p53‐independent mechanism.     

Direct Self‐Assembly of a 2D and 3D Star of David

Two‐ and three‐dimensional metallosupramolecules shaped like a Star of David were synthesized by the self‐assembly of a tetratopic pyridyl ligand with a 180° diplatinum(II) motif and Pd^II ions, respectively. In contrast to other strategies, such as template‐directed synthesis and stepwise self‐assembly, this design enables the formation of 2D and 3D structures in one step and high yield. The structures were characterized by both one‐dimensional (¹H, ¹³C, ³¹P) and two‐dimensional (COSY, NOESY, DOSY) NMR spectroscopy, ESI‐MS, ion‐mobility mass spectrometry (IM–MS), AFM, and TEM. The stabilities of the 2D and 3D structures were measured and compared by gradient tandem mass spectrometry (gMS²). The high stability of the 3D Star of David was correlated to its high density of coordination sites (DOCS).     

Anticancer Potency and Multidrug‐Resistant Studies of Self‐Assembled Arene–Ruthenium Metallarectangles

A suite of three tetraruthenium metallacycles have been obtained from [2+2] self‐assemblies between N,N′‐Di‐(4‐pyridyl)‐1,4,5,8‐naphthalenetetracarbo–xydiimide ( 4 ) and one of the three dinuclear arene ruthenium clips, (η⁶‐p‐iPrC₆H₄Me)₂Ru₂(OO∩OO)][OTf]₂ (OO∩OO=oxalate 1 , 2,5‐dioxydo‐1,4‐benzoquinonato (dobq) 2 , 5,8‐dihydroxy‐1,4‐naphthaquinonato (donq) 3 ; OTf=triflate). All complexes were isolated in good yield (>85 %) as triflate salts and were fully characterized by using ¹H NMR and UV/Vis spectroscopies, and high‐resolution electrospray mass spectrometry. A single crystal of the metallarectangle 5 was suitable for X‐ray diffraction structural characterization. The biological activities of the metallacycles were determined by using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assays, establishing their in vitro anticancer properties. Our results show that for the AGC (gastric cancer) cell lines, the cytotoxicity of (donq)‐containing SCC 7 exceeds that of cisplatin, which was used as a control. For HCT15 (colon cancer) cell lines, the cytotoxicity is comparable to both cisplatin and doxorubicin. An in vivo hollow fiber model was used to show growth‐inhibitory activity against HCT15 and image‐based cytometry experiments indicated that 7 induced apoptosis as the mode of cell death. Complex 7 also showed significant antitumor activity for multidrug‐resistant HCT15/CLO2 cell lines, for which doxorubicin was ineffective.     

Metal‐Directed Self‐Assembly of a Polyoxometalate‐Based Molecular Triangle: Using Powerful Analytical Tools to Probe the Chemical Structure of Complex Supramolecular Assemblies

A polyoxometalate‐based molecular triangle has been synthesized through the metal‐driven self‐assembly of covalent organic/inorganic hybrid oxo‐clusters with remote pyridyl binding sites. The new metallomacrocycle was unambiguously characterized by using a combination of ¹H NMR spectroscopy, 2D diffusion NMR spectroscopy (DOSY), electrospray ionization travelling wave ion mobility mass spectrometry (ESI‐TWIM‐MS), small‐angle X‐ray scattering (SAXS) and molecular modelling. The collision cross‐sections obtained from TWIM‐MS and the hydrodynamic radii derived from DOSY are in good agreement with the geometry‐optimized structures obtained by using theoretical calculations. Furthermore, SAXS was successfully employed and proved to be a powerful technique for characterizing such large supramolecular assemblies.     

Anion Directed Self‐Assembly of One‐Dimensional and Two‐Dimensional Coordination Polymers Containing Bridging Diphosphine Ligands

The reactions of 1,2‐bis(diphenylphosphanyl)ethane (dppe) with different silver(I) salts facilitated the formation of 1D and 2D coordination polymers, [Ag(dppe)(OAc)]_n · nH₂O ( 1 ) and [Ag₂(dppe)_1.5(NO₃)₂]_n ( 2 ), respectively. The complexes were characterized by elemental analysis, ATR‐IR spectroscopy, ¹H NMR, ¹³C NMR, and ³¹P NMR spectroscopy, and single‐crystal X‐ray diffraction. Structural analysis revealed that complex 1 exhibits a 1D infinite wavy structure, in which each silver(I) ion is bridged by dppe ligands. Structure 2 has a 2D topologically promising architecture that displays a 6.6.6 graphitic net, which corresponds to hnd topology. The nitrate ions and dppe ligands are in a μ₂ bridging mode and support the formation of this net. Moreover, significant π–π interactions between the phenyl rings in the apertures of (6,3) grid stabilized complex 2 .     

Sterically‐Directed Consecutive and Size‐Selective Self‐Assembly of Palladium Diphosphane Complexes with an Ar‐BIAN Ligand: Unexpected Formation of Pentameric and Hexameric Aggregates

The coordination properties of N,N′‐bis[4‐(4‐pyridyl)phenyl]acenaphthenequinonediimine (L¹) and N,N′‐bis[4‐(2‐pyridyl)phenyl]acenaphthenequinonediimine (L²) were investigated in self‐assembly with palladium diphosphane complexes [Pd(P^P)(H₂O)₂](OTf)₂ (OTf=triflate) by using various analytical techniques, including multinuclear (¹H, ¹⁵N, and ³¹P) NMR spectroscopy and mass spectrometry (P^P=dppp, dppf, dppe; dppp=bis(diphenylphosphanyl)propane, dppf= bis(diphenylphosphanyl)ferrocene, and dppe=bis(diphenylphosphanyl)ethane). Beside the expected trimeric and tetrameric species, the interaction of an equimolar mixture of [Pd(dppp)]²⁺ ions and L¹ also generates pentameric aggregates. Due to the E/Z isomerism of L¹, a dimeric product was also observed. In all of these species, which correspond to the general formula [Pd(dppp)L¹]_n(OTf)_2n (n=2–5), the L¹ ligand is coordinated to the Pd center only through the terminal pyridyl groups. Introduction of a second equivalent of the [Pd(dppp)]²⁺ tecton results in coordination to the internal, sterically more encumbered chelating site and induces enhancement of the higher nuclearity components. The presence of higher‐order aggregates (n=5, 6), which were unexpected for the interaction of cis‐protected palladium corners with linear ditopic bridging ligands, has been demonstrated both by mass‐spectrometric and DOSY NMR spectroscopic analysis. The sequential coordination of the [Pd(dppp)]²⁺ ion is attributed to the dissimilar steric properties of the two coordination sites. In the self‐assembled species formed in a 1:1:1 mixture of [Pd(dppp)]²⁺/[Pd(dppe)]²⁺/L¹, the sterically more demanding [Pd(dppp)]²⁺ tectons are attached selectively to the pyridyl groups, whereas the more hindered imino nitrogen atoms coordinate the less bulky dppe complexes, thus resulting in a sterically directed, size‐selective sorting of the metal tectons. The propensity of the new ligands to incorporate hydrogen‐bonded solvent molecules at the chelating site was confirmed by X‐ray diffraction studies.     

Self‐Assembly of 3,6‐Bis(4‐triazolyl)pyridazine Ligands with Copper(I) and Silver(I) Ions: Time‐Dependant 2D‐NOESY and Ultracentrifuge Measurements

Two 3,6‐bis(R‐1H‐1,2,3‐triazol‐4‐yl)pyridazines (R=mesityl, monodisperse (CH₂ CH₂O)₁₂CH₃) were synthesized by the copper(I)‐catalyzed azide–alkyne cycloaddition and self‐assembled with tetrakis(acetonitrile)copper(I) hexafluorophosphate and silver(I) hexafluoroantimonate in dichloromethane. The obtained copper(I) complexes were characterized in detail by time‐dependent 1D [¹H, ¹³C] and 2D [¹H‐NOESY] NMR spectroscopy, elemental analysis, high‐resolution ESI‐TOF mass spectrometry, and analytical ultracentrifugation. The latter characterization methods, as well as the comparison to analog 3,6‐di(2‐pyridyl)pyridazine (dppn) systems and their corresponding copper(I) and silver(I) complexes indicated that the herein described 3,6‐bis(1H‐1,2,3‐triazol‐4‐yl)pyridazine ligands form [2×2] supramolecular grids. However, in the case of the 3,6‐bis(1‐mesityl‐1H‐1,2,3‐triazol‐4‐yl)pyridazine ligand, the resultant red‐colored copper(I) complex turned out to be metastable in an acetone solution. This behavior in solution was studied by NMR spectroscopy, and it led to the conclusion that the copper(I) complex transforms irreversibly into at least one different metal complex species.     

Hydroacridines: Part 23. 1H and 13C NMR spectra of sym‐octahydroacridine,its 9‐(3‐pyridyl) and 9‐(4‐pyridyl) derivatives and the corresponding N(10)‐oxides. An experimental approach to the diamagnetic anisotropy of the pyridine nucleus

The complete ¹H NMR chemical shift assignments of 1,2,3,4,5,6,7,8‐octahydroacridine ( 1 ), 1,2,3,4,5,6,7,8‐octahydro‐9‐(3‐pyridyl)acridine ( 2 ), 1,2,3,4,5,6,7,8‐octahydro‐9‐(4‐pyridyl)acridine ( 3 ) and the corresponding N(10)‐oxides 1a , 2a and 3a , respectively, were achieved on the basis of 400 MHz ¹H NMR spectra and proton–proton decoupling, HMQC and NOEDIFF experiments. The spectral data for the above compounds provided the first experimental evidence of the difference in the anisotropy effect of the two non‐symmetrical moieties of the pyridine nucleus, and allowed us to ascertain that the shielding effect of the moiety defined by the C(2′)—N—C(6′) atoms is weaker than that of the C(3′)—C(4′)—C(5′) moiety. The ¹³C NMR spectra of 1 – 3 and 1a – 3a and the effect of N(10)‐oxidation on the ¹³C NMR chemical shifts are also discussed. The N‐oxidation of 2 and 3 with m‐chloroperbenzoic acid occurred regiospecifically, affording the N(10)‐oxides 2a and 3a free of N(1′)‐oxide isomers. Copyright © 2002 John Wiley & Sons, Ltd.     

Regioregular head‐to‐tail poly(6‐alkylpyridine‐2,5‐diyl)s and a new type of packing structure of the polymer in the solid state

New regioregular head‐to‐tail type poly(6‐alkylpyridine‐2,5‐diyl)s (P6RPys; R = nonyl, dodecyl, and pentadecyl) were prepared by organometallic polycondensation. The head‐to‐tail (HT) content in the polymers was higher than 95%, as revealed by ¹H NMR spectroscopy. Powder X‐ray diffraction data of HT‐P6RPys indicated that P6RPys formed a new type of structure composed of an alternating end‐to‐end packed unit and an interdigitation packed unit. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 215–222, 2005     

NMR Investigation of Imidazolium‐Based Ionic Liquids and Their Aqueous Mixtures

¹H and ¹³C NMR spectroscopy is employed to investigate the interaction of water with two imidazolium‐based ionic liquids (ILs), 1‐hexyl‐3‐methylimidazolium bromide ([C₆mim]Br) and 1‐octyl‐3‐methylimidazolium bromide ([C₈mim]Br), at IL concentrations well above the critical aggregation concentration (CAC). The results are compared with those of the neat samples. To this aim, a detailed analysis of the changes in the ¹H chemical shifts, ¹³C relaxation parameters, and 2D ROESY data due to the presence of water is performed. The results for both neat ILs are consistent with a packed structure where head‐to‐head, head‐to‐tail, and tail‐to‐tail contacts occur and where the site of maximal mobility restriction is at the polar head. At the lowest investigated water content, the presence of water influences mainly the environment around the IL polar head, slowing down the motional dynamics of the aromatic ring with respect to the alkyl chain. At higher water contents this difference diminishes, the motional freedom of the whole molecule increasing. The presence of ROESY cross‐peaks between protons in the polar and apolar IL regions, as well as between protons in non‐neighboring alkyl groups, at all investigated water contents suggests that the alkyl tails are not fully segregated in hydrophobic domains, as expected for micelle‐like structures.     

A Simple and Efficient Procedure for Synthesis of Optically Active 1,2,4‐Triazolo‐[3,4‐b]‐1,3,4‐Thiadiazole Derivatives Containing l‐Amino Acid Moieties

Some new and optically active 1,2,4‐triazolo thiadiazoles bearing N‐phthaloyl‐l ‐amino acids were synthesized by reaction of 4‐amino‐5‐(3‐ or 4‐)pyridyl‐3‐mercapto‐(4H)‐1,2,4‐triazoles with N‐phthaloyl‐l ‐amino acids in the presence of phosphorus oxychloride. All the newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR and elemental analysis.     

Synthesis and Crystal Structure of [Pb(trz)(tfpb)(H2O)]: a Lead(II) Complex Containing 2,4,6‐Tris(2‐pyridyl)‐1,3,5‐triazine and 4,4,4‐Trifluoro‐1‐phenyl‐1,3‐butandionate

[Pb(trz)(tfpb)(H₂O)] ( 1 ) (trz and tfpb are the abbreviations of 2,4,6‐tris(2‐pyridyl)‐1,3,5‐triazine and 4,4,4‐trifluoro‐1‐phenyl‐1,3‐butandionate, respectively) have been synthesized and characterized by elemental analysis and IR, ¹H NMR, spectroscopy. The single‐crystal structure of 1 shows the coordination number of the Pb²⁺ ions is eight with three N‐donor atoms from a “trz” ligand and four O‐donors from the dionate ligand and one molecule of water. The supramolecular features in this complex are guided by lone pair activity and control of strong hydrogen bonds, weak directional intermolecular interactions and aromatic π‐π stacking interactions.     

Planar 2‐Pyridyl‐1,2,3‐triazole Derived Metallo‐ligands: Self‐assembly with PdCl2 and Photocatalysis

Self‐assembled metallosupramolecular architectures (MSAs) with built‐in functionalities such as light‐harvesting metal centers are a promising approach for developing emergent properties within discrete molecular systems. Herein we describe the synthesis of two new but simple “click” ligands featuring a bidentate 2‐pyridyl‐1,2,3‐triazole chelate pocket linked to a monodentate pyridyl (either 3‐ or 4‐substituted, L1 and L2 ) unit. The ligands and the corresponding four Pd^IIand Pt^IImetallo‐ligands ( Pd1 , Pd2 , Pt1 and Pt2 ) were synthesized and characterized using nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization mass spectrometry (ESI‐MS), and X‐ray crystallography. Solid‐state characterization of the series of ligands and metallo‐ligands revealed that these compounds display a co‐planar conformation of all the aryl units. The Pt^IIcontaining metallo‐ligands ( Pt1 and Pt2 ) were found to assemble into square ( Sqr ) and triangular ( Tri ) shaped architectures when combined with neutral PdCl₂ linker units. Additionally, the ability of the Pt^IImetallo‐ligands and Tri to photocatalyze the cycloaddition of singlet oxygen to anthracene was investigated.