Synthesis and structure of tris(triphenyltin)benzene-1,3,5-tricarboxylate and its tri-DMSO adduct

The molecular structure of (Ph₃SnO₂C)₃C₆H₃ reveals distorted tetrahedral C₃O geometries for each tin atom. No intermolecular Sn...O associations occur between the molecules so that the trinuclear molecule may be considered monomeric. An increase in coordination number at tin is indicated by ¹¹⁹Sn NMR measurements conducted in d₆-DMSO solution and this has been confirmed by a structure analysis of (DMSO·Ph₃SnO₂C)₃C₆H₃·2 DMSO. In this structure, the tin atom geometries are distorted trigonal bipyramidal, existing within trans-C₃O₂ donor sets. Thus, while is it possible for the tin atoms to increase their coordination numbers in (Ph₃SnO₂C)₃C₆H₃, molecular aggregation to form polymeric arrays is precluded, most likely due to steric constraints.

Pressure-induced phase transition in hydrogen-bonded supramolecular adduct formed by cyanuric acid and melamine

Single-crystal samples of the 1:1 adduct between cyanuric acid and melamine (CA·M), an outstanding case of noncovalent synthesis, have been studied by Raman spectroscopy and synchrotron X-ray diffraction in a diamond anvil cell up to pressures of 15 GPa. The abrupt changes in Raman spectra around 4.4 GPa have provided convincing evidence for pressure-induced structural phase transition. This phase transition was confirmed by angle dispersive X-ray diffraction (ADXRD) experiments to be a space group change from C2/m to its subgroup P2₁/m. On release of pressure, the observed transition was irreversible, and the new high-pressure phase was fully preserved at ambient conditions. We propose that this phase transition was due to supramolecular rearrangements brought about by changes in the hydrogen bonding networks.

Melamine–melem adduct phases: Investigating the thermal condensation of melamine

By studying the thermal condensation of melamine, we have identified three solid molecular adducts consisting of melamine C3N3(NH2)3 and melem C6N7(NH2)3 in differing molar ratios. We solved the crystal structure of 2 C3N3(NH2)3⋅C6N7(NH2)3 (1; C2/c; a=21.526(4), b=12.595(3), c=6.8483(14) Å; β=94.80(3)°; Z=4; V=1850.2(7) Å3), C3N3(NH2)3⋅C6N7(NH2)3 (2; Pcca; a=7.3280(2), b=7.4842(2), c=24.9167(8) Å; Z=4; V=1366.54(7) Å3), and C3N3(NH2)3⋅3 C6N7(NH2)3 (3; C2/c; a=14.370(3), b=25.809(5), c=8.1560(16) Å; β=94.62(3)°; Z=4; V=3015.0(10) Å3) by using single-crystal XRD. All syntheses were carried out in sealed glass ampoules starting from melamine. By variation of the reaction conditions in terms of temperature, pressure, and the presence of ammonia-binding metals (europium) we gained a detailed insight into the occurrence of the three adduct phases during the thermal condensation process of melamine leading to melem. A rational bulk synthesis allowed us to realize adduct phases as well as phase separation into melamine and melem under equilibrium conditions. A solid-state NMR spectroscopic investigation of adduct 1 was conducted.

Hydrolysis of bis((trimethylsilyl)methyl)tin dihalides. Crystallographic and spectroscopic study of the hydrolysis pathway

The synthesis and characterization by multinuclear NMR spectroscopy of the diorganotin dihalides (Me₃SiCH₂)₂SnX₂ (1, X = Cl; 2, X = Br), the diorganotin dichloride water adduct (Me₃SiCH₂)₂SnCl₂·H₂O (1a), the dimeric tetraorganodistannoxanes [(Me₃SiCH₂)₂(X)SnOSn(Y)(CH₂SiMe₃)₂]₂ (3, X = Y = Cl; 4, X = Br, Y = OH; 5, X = Br, Y = F; 6, X = Y = OH; 8, X = Cl, Y = OH), and the molecular diorganotin oxide cyclo-[(Me₃SiCH₂)₂SnO]₃ (7) are reported. The structures in the solid state of compounds 1a, 3, 6, and 7 were determined by single-crystal X-ray analysis. In toluene solution, the hydroxy-substituted tetraorganodistannoxane 6 is in equilibrium with the diorganotin oxide 7 and water. The eight-membered diorganotin oxide cyclo-[(Me₃SiCH₂)₂SnO]₄ (7a) is proposed to be involved in this equilibrium. On the basis of the results of this and previous works, a general hydrolysis pathway is developed for diorganotin dichlorides containing reasonably bulky substituents.

Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Synthesis, x-ray structure of ferrocene bearing Bis(Zn-cyclen) complexes and the selective electrochemical sensing of TpT

The new ligand, [Fc(cyclen)₂] (5) (Fc=ferrocene, cyclen=1,4,7,10-tetraazacyclododecane), and corresponding Zn^II complex receptor, [Fc{Zn(cyclen)(CH₃OH)}₂](ClO₄)₄ (1), consisting of a ferrocene moiety bearing one Zn^II-cyclen complex on each cyclopentadienyl ring, have been designed and prepared through a multi-step synthesis. Significant shifts in the ¹H NMR signals of the ferrocenyl group, cf. ferrocene and a previously reported [Fc{Zn(cyclen)}]²⁺ derivative, indicated that the two Zn^II-cyclen units in 1 significantly affect the electronic properties of the cyclopentadienyl rings. The X-ray crystal structure shows that the two positively charged Zn^II-cyclen complexes are arranged in a trans like configuration, with respect to the ferrocene bridging unit, presumably to minimise electrostatic repulsion. Both 5 and 1 can be oxidized in 1:4 CH₂Cl₂/CH₃CN and Tris-HCl aqueous buffer solution under conditions of cyclic voltammetry to give a well defined ferrocene-centred (Fc⁰/+) process. Importantly, 1 is a highly selective electrochemical sensor of thymidilyl(3′-5′)thymidine (TpT) relative to other nucleobases and nucleotides in Tris-HCl buffer solution (pH 7.4). The electrochemical selectivity, detected as a shift in reversible potential of the Fc⁰/+ component, is postulated to result from a change in the configuration of bis(Zn^II-cyclen) units from a trans to a cis state. This is caused by the strong 1:1 binding of the two deprotonated thymine groups in TpT to different Zn^II centres of receptor 1. UV-visible spectrophotometric titrations confirmed the 1:1 stoichiometry for the 1:TpT adduct and allowed the determination of the apparent formation constant of 0.89±0.10×10⁶ M⁻¹ at pH 7.4.

Rapid domino [3+2] cycloaddition, [4+2] cycloreversion, ring-opening and aromatisation of a fused oxanorbornane substrate

Heating a dioxa-bridged diene with a cyclobutane epoxide for 10 min under microwave conditions (150 °C) gave an unexpected aryloxanorbornane product (20%). This adduct is proposed to occur via a [3+2] dipolar cycloaddition, retro-Diels-Alder reaction, ring-opening and subsequent aromatisation.

Cisplatin-induced formation of biocompatible and biodegradable polypeptide-based vesicles for targeted anticancer drug delivery

Novel cisplatin (CDDP)-loaded, polypeptide-based vesicles for the targeted delivery of cisplatin to cancer cells have been prepared. These vesicles were formed from biocompatible and biodegradable maleimide-poly(ethylene oxide)114-b-poly(L-glutamic acid)12 (Mal-PEG114-b-PLG12) block copolymers upon conjugation with the drug itself. CDDP conjugation forms a short, rigid, cross-linked, drug-loaded, hydrophobic block in the copolymer, and subsequently induces self-assembly into hollow vesicle structures with average hydrodynamic diameters (Dh) of ∼ 270 nm. CDDP conjugation is critical to the formation of the vesicles. The reactive maleimide-PEG moieties that form the corona and inner layer of the vesicles were protected via formation of a reversible Diels-Alder (DA) adduct throughout the block copolymer synthesis so as to maintain their integrity. Drug release studies demonstrated a low and sustained drug release profile in systemic conditions (pH = 7.4, [Cl(-)] = 140 mM) with a higher "burst-like" release rate being observed under late endosomal/lysosomal conditions (pH = 5.2, [Cl(-)] = 35 mM). Further, the peripheral maleimide functionalities on the vesicle corona were conjugated to thiol-functionalized folic acid (FA) (via in situ reduction of a novel bis-FA disulfide, FA-SS-FA) to form an active targeting drug delivery system. These targeting vesicles exhibited significantly higher cellular binding/uptake into and dose-dependent cytotoxicity toward cancer cells (HeLa) compared to noncancerous cells (NIH-3T3), which show high and low folic acid receptor (FR) expression, respectively. This work thus demonstrates a novel approach to polypeptide-based vesicle assembly and a promising strategy for targeted, effective CDDP anticancer drug delivery.