Synthesis and Single Crystal Structure of a New Dinuclear Copper(II) Complex of 1,5-Bis(8-oxaquinoline)-3-methylpentane

A new flexible ligand, 1,5-bis(8-oxaquinoline)-3-methylpentane (C5MeOQ), was synthesized and used in the preparation of the new dinuclear copper(II) complex 1: [Cu₂(μ-OMe)₂(μ-C5MeOQ)(NO₃)₂]. Single crystal X-ray analysis revealed that complex 1 contains dinuclear Cu(II) units with bridging methoxo groups. The ligand, C5MeOQ, takes on a bent conformation in order to connect to and complete the square planar coordination environment of both copper centers; and one of the two Cu(II) centers adopts a distorted square planar configuration as a result of the ligand conformation. The magnetic properties of complex 1 were investigated by variable-temperature magnetic susceptibility measurements in the 100–300 K range. Interestingly, the susceptibility data for complex 1 reveals that the compound is diamagnetic, suggesting the presence of very strong antiferromagnetic coupling interactions between the adjacent Cu(II) centers.     

Multi-selective one dimensional proton NMR experiments for rapid screening and binding affinity measurements

High-throughput ligand-based proton NMR screening performed in the presence of a spy molecule and a control molecule is a valuable tool for identifying drug leads. A limitation of the technique is represented by the severe overlap encountered in the screening of large chemical mixtures. An approach for overcoming this overlap problem is the use of multi-selective R(1) filtered and COSY or TOCSY experiments. Application of this methodology to compounds binding to the Sudlow site I of human serum albumin is presented. The screening is performed by simply monitoring the intensity of two signals. The precise measurement of the relative intensity of the two resonances permits determination of the binding constant of the NMR-hit. For a simple competition binding mechanism, the rapidly-derived NMR binding constants are in good agreement with the values derived from full-titration ITC and fluorescence spectroscopy measurements.     

Assembly of a supramolecular capsule on a molecular printboard

A molecular capsule based on ionic interactions between two oppositely charged calix[4]arenes, 1 and 2, was assembled both in solution and on a surface. In solution, the formation of the equimolar assembly 1.2 was studied by (1)H NMR, ESI-MS, and isothermal titration calorimetry, giving an association constant (K(a)) of 7.5 x 10(5) M(-1). A beta-cyclodextrin self-assembled monolayer (beta-CD SAM) on gold was used as a molecular printboard to anchor the tetraguanidinium calix[4]arene (2). The binding of tetrasulfonate calix[4]arene 1 was monitored by surface plasmon resonance spectroscopy. Rinsing of the surface with a high ionic strength aqueous solution allows the removal of the tetrasulfonate calix[4]arene (1), while by rinsing with 2-propanol it is possible to achieve the complete desorption of the tetraguanidinium calix[4]arene (2) from the beta-CD SAM. The K(a) for the capsule formation on a surface is 3.5 x 10(6) M(-1), thus comparing well with the K(a) determined in solution.     

Reactivity of the tetrahydroborate copper(I) complexes [(PR3)2Cu(η2-BH4)] (R = Ph,Cy) toward CO2, COS,and SCNPh

CO₂, COS, and SCNPh react under very mild conditions with the copper(I)-tetrahydroborate complexes [(PR₃)₂Cu(η²-BH₄)] (R = Ph, Cy); CO₂ and COS give the complexes [(PR₃)₂Cu(η²-O₂CH)] and [(PR₃)₂Cu(η²-OSCH)] respectively, whereas SCNPh gives the η²-dithiocarbamate complexes [(PR₃)₂Cu-(η²-S₂CNHPh)]. Addition of PPh₃ under CO₂ to solutions of [(PPh₃)₂Cu-(η²-BH₄)] gives [(PPh₃)₃Cu(η¹-O₂CH)] while addition of PPh₃ and NBu₄ClO₄ under CO₂ gives [(PPh₃)₃Cu(η-O₂CH)Cu(PPh₃)₃] ClO₄.     

Selective synthesis of 14β-amino taxanes

The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylates and tosyl azide. In particular, tosyl azide gave the corresponding 7-BOC- and 7-TES-13-oxo-14β-azido-baccatin III. Alternatively, the last compound was prepared via NaN₃ induced azidation of the 13-silyl enol ether of 7-TES-13-oxo-baccatin III under oxidative (cerium ammonium nitrate) conditions. The 13-silyl enol ether was obtained in a multistep process by DBU induced silylation of 7-TES-13-oxo-baccatin III. The 7-TES-13-oxo-14β-azido-baccatin III was used as a key intermediate for the synthesis of a new family of antitumour taxanes containing amino based functional groups at the C-14 position, such as: 14β-azido, 14β-amino, 14β-amino 1, 14-carbamate, 14β-amino 1, 14-thiocarbamate, and 14β-amino N-tert-butoxycarbonyl-1,14-carbamate.     

Binuclear wirelike dimers based on ruthenium(II)-bipyridine units linked by ethynylene-oligothiophene-ethynylene bridges

The syntheses, structural characteristics, electrochemical behavior, ground-state spectra, photophysical properties, and transient absorption (TA) spectra in CH(3)CN solvent are reported for binuclear [(bpy)(2)Ru(bpy-E(T)(n)()E-bpy)Ru(bpy)(2)](4+) complexes, Ru(bpyT(n)bpy)Ru, where the Ru-based units are connected by alternating 3,4-dibutylthiophene (DBT')/thiophene (T') fragments linked via ethynyl groups (E) to bpy ligands at the 5-position (bpy is 2,2'-bipyridine). The ligand bpyT(3)bpy represents a module containing DBT'/T'/DBT' subunits, and bpyT(5)bpy accounts for a DBT'/T'/DBT'/T'/DBT' pattern. The syntheses and electrochemical and spectroscopic (emission and TA) properties in CH(2)Cl(2) solvent of the bpyT(n)()bpy ligands are likewise reported. The behavior of the Ru(bpyT(n)bpy)Ru dimers has been compared to that of the bpyT(n)bpy ligands and to that of a related mononuclear complex, [(bpy)(2)Ru(bpy-E-DBT')](2+), Ru(bpyDBT'). For the dimeric complexes, the electrochemical results show that the first reduction step takes place at the bpy ligand(s) bearing an ethynylene group, the first oxidation step is thiophene-centered, and further oxidation involves the metal centers, which are only weakly interacting. The photophysical and TA results for the Ru(bpyT(n)bpy)Ru dimers account for the presence of low-lying oligothiophene-centered (3)pi,pi levels, while higher-lying metal-ligand charge transfer ((3)MLCT) levels are thermally accessible only for the case of Ru(bpyT(3)bpy)Ru; the possible role of charge separation (CS) levels (from oxidation at the thiophene bridge and reduction at one of the coordinated bpy's) is also discussed.     

The dithianyl group as a synthon in porphyrin chemistry: condensation reactions and preparation of formylporphyrins under basic conditions

Vilsmeier formylation is one of the most widely used substitution reactions for the functionalization of porphyrins. However, its utility is limited by the electrophilic/acidic reaction conditions, deactivation of the aromatic system and regiochemical problems, the requirement for metal complexes and necessity for subsequent demetalation under harsh conditions, and low functional group tolerance. To overcome these limitations, the dithianyl group has been utilized as a latent formyl synthon in porphyrin chemistry. 2-Formyl-1,3-dithiane can be used directly in pyrrole condensation reactions to regioselectively yield porphyrins with up to four dithianyl residues. Likewise, 5-dithianyldipyrromethane could be prepared quantitatively as a key building block for various porphyrin condensation reactions yielding the respective free base formylporphyrins after deprotection. Additionally, dithianyllithium can be used as a reagent for the direct aromatic substitution of metallo- and free base porphyrins under nucleophilic conditions.     

Enantiomeric analysis of rivastigmine in pharmaceuticals by cyclodextrin-modified capillary zone electrophoresis

Chiral separation method development is usually very time-consuming due to the diversity in chemical structures of pharmaceutical drug substances as well as the suitable separation conditions and the problem to choose the appropriate chiral selector. This paper shows capillary zone electrophoresis (CZE) which was developed for chiral separation of a basic compound - rivastigmine (RIV) using 30 cm × 50 μm i.d. polyacrylamide (PAA)-coated fused-silica capillary (effective length 20 cm), amine-modified phosphate buffer of pH 2.5 and sulfated-β-CD (S-β-CD) as chiral selector. Other selected native or derivatized cyclodextrins (CDs) were also tested: β-CD (5, 30 mM), carboxymethyl-β-CD (5, 30 mM), dimethyl-β-CD (15 mM), hydroxypropyl-β-CD (5, 30 mM), hydroxypropyl-α-CD (5, 30 mM) and hydroxypropyl-γ-CD (5, 30 mM). Complete enantiomeric separation of RIV was achieved at 20 kV, 18 °C and detection at 200 nm within 8 min with R.S.D. for the absolute migration time reproducibility of less than 2.1%. Rectilinear calibration range was 5.0-500.0 μM of each enantiomer (r = 0.9994-0.9995). The CZE method proposed was used for the control of chiral purity of pharmaceutically active S-RIV and for the analysis of Exelon caps preparation.     

Tandem Michael‐addition/cyclization synthesis and EGFR kinase inhibition activity of pyrido[2,3‐d]pyrimidin‐7(8H)‐ones

5‐Methoxy and 5‐anilinopyrido[2,3‐d]pyrimidin‐7(8H)‐ones 2a‐2f were obtained by a tandem Michael addition‐cyclization reaction of methanol and anilines with pyrimidinylpropynoate 5. Methoxy derivative 2a was obtained in 62% yield by treatment of 5 with methanol and potassium carbonate. Anilino derivatives 2b‐2f were prepared in 31–71% yields by reacting 5 with the corresponding anilines in refluxing methanol. This methodology accomplishes Michael‐addition and pyridopyrimidinone ring formation in one‐pot and affords the desired products in reasonable yield without chromatography. Propynoate 5 did not react with 4‐cyanoaniline under these conditions. Reaction of 5 with 2‐aminopyridine gave the unexpected arylpyrido[2,3‐d]pyrimidinone 8 in 58% yield and reaction of 5 with imidazole afforded Michael‐adduct 9 in 69% yield. Compounds 2a and 5 were submicromolar inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase.     

2(H)-1,4-Oxazin-2-ones as ambident azadienes

3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4, 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and selectively with both electron rich and electron poor dienophiles.