Platinum metallodrug-protein binding studies by capillary electrophoresis-inductively coupled plasma-mass spectrometry: characterization of interactions between Pt(II) complexes and human serum albumin

Characterizing how platinum metallocomplexes bind to human serum albumin (HSA) is essential in evaluating anticancer drug candidates. Using cisplatin as a reference complex, the application of capillary electrophoresis (CE) to reliably assess drug/HSA interactions was validated. Since this complex is small compared to the size of the protein, the binding response could only be recognized when applying CE coupled to a (platinum) metal-specific mode of detection, namely inductively coupled plasma-mass spectrometry (ICP-MS). This coupling allowed for confirmation of a specific affinity of cisplatin and novel Pt complexes to HSA, measurement of the kinetics of binding reactions, and determination of the number of drug molecules attached to the protein. As the cisplatin/HSA molar ratio increased, the reaction rate became faster with a maximum on the kinetic curve appearing at about 50 h of incubation at 20 times excess of cisplatin. The reaction was characterized as a pseudo-first order reaction with the rate constant k = 0.003 min(-1) at 37 degrees C. When incubated with a 20-fold excess of cisplatin, HSA bound up to 10 mol of Pt per mol of the protein. This is indicative for a strong metal-protein coordination occurring at several HSA sites other than the only protein cysteine residue. Structural analogs of cisplatin, bearing aminoalcohol ligands, showed comparable protein binding reactivity and stoichiometry but a common equilibrium was not reached even after one week of incubation. Also apparent was a two-step mechanism of the binding reaction. Results demonstrated the suitability of CE-ICP-MS as a rapid assay for high-throughput studying of drug/HSA interactions.     

Functional polymers and sequential copolymers by phase transfer catalysis. XXVIII. Synthesis and characterization of alternating block copolymers and polyformals of polyisobutylene and aromatic polyether sulfone

Alternating—i.e., -(A-B)_n- type—block copolymers of polyisobutylene (PIB) and aromatic polyether sulfone (PSU) have been prepared by phase transfer catalyzed Williamson polyetherification of α,ω-di(phenol)PIB with α,ω-di(chloroallyl)- or -(bromobenzyl)PSU. Block copolymers of the two prepolymers were also synthesized by the phase transfer catalyzed polyetherification of methylene chloride with α,ω-di(phenol)PIB and α,ω-di(phenol)PSU (bisphenol-A-terminated PSU). This method leads to -[(A)_x-(B)_y]_n- block copolymers with formal linkages between segments. At sufficiently high segment lengths, both types of block copolymers exhibit two distinct T_gs, indicating phase separation into rubbery PIB and glassy PSU domains.     

Photophysical properties of a C6 hydrocarbon linked porphyrin dimer

The synthesis and characterisation of a C₆ hydrocarbon linked porphyrin dimer and its zinc complex is described. From fluorescence quantum yields and excited singlet and triplet state lifetimes, recorded for the dimers and the corresponding monomer species, it is suggested that the dimeric porphyrins exist in solution in open and closed conformations. The open conformations retain photophysical properties similar to those of the relevant monomeric species but the closed conformations do not fluoresce.     

Functional polymers and sequential copolymers by phase transfer catalysis. XXVI. Synthesis and characterization of thermotropic liquid crystalline polypodants

Thermotropic liquid crystalline (LC) polyethers and copolyethers have been synthesized from 4,4′-dihydroxy-α-methylstilbene (HMS) and α,ω-dichlorooligo(oxyethylene)s having between 2 and 5 as well as 8.7 oxyethylene units. Copolyethers were prepared from a 1:1 mol/mol ratio of two dissimilar spacers. These polymers have been prepared by a phase transfer catalyzed (PTC) polyetherification of bisphenols with these electrophiles by utilizing 50 mol% tetrabutylammonium hydrogen sulfate per phenol group. Kinetic experiments with either 5 or 50 mol% catalyst vs phenol groups in the polyetherification of 4,4%-isopropylidenediphenol with 2-chloroethyl ether have shown that a change in catalyst primarily affects the rate of reaction, with 50 mol % being faster. The prepared polyethers and copolyethers are soluble in common organic solvents. Both polyethers and copolyethers are crystalline. Polymers prepared to contain tetraoxyethylene spacers exhibit monotropic LC behavior. Copolymers prepared to contain tri- and tetraoxyethylene spacers (1 : 1 mol/mol) [PE34] were the only polymers exhibiting enantiotropic LC behavior. Longer spacers tend to destabilize the phase transitions, as suggested by the dependence of thermal transition temperatures upon the differential scanning calorimeter rate. All prepared polymers act as podants in solution, measured by picrate extraction experiments. Solid state complexes have been prepared from the polymer with a pentaoxyethylene spacer [PE5] and PE34 with LiCF₃SO₃. PE5 can dissolve LiCF₃SO₃ in the range of 0.21–2.2 mol salt/mol polymer (m.r.u.) [S/P] without the observation of free salt. PE5 complexes of/or below S/P of 0.43, upon annealing at room temperature, exhibited the two melting transitons observed in the polymer alone. PE5 complexes of/or above S/P of 0.77 only exhibited a T_g. The T_g of PE5 complexes were found to change nonlinearly with S/P, while T_m1 changed linearly. T_m2 was independent of S/P. Only one complex with PE34 gave two transitions (T_m2,Tⁱ) in dynamic DSC experiments. Other PE34 complexes followed a behavior similar to PE5 complexes.     

Synthesis of new mono-functionalised tetrathiafulvalene derivatives by reactions of etrathiafulvalenyllithium with aldehydes and ketones: X-ray crystal structures of TTF-CMe(OH)Fc, TTF-CMe(OMe)Fc and TTF-CH(OMe)TTF (Fc = ferrocenyl)

Reactions of tetrathiafulvalenyllithium (TTF-Li) with a range of aldehydes and ketones have been explored for the first time, to provide an efficient route to mono-functionalised TTF derivatives of general formulae TTF-CH(OH)R (R = alkyl, phenyl, tetrathiafulvalenyl and ferrocenyl) and TTF-CR(OH)R′ (R = alkyl, phenyl, R′ = alkyl, phenyl, tetrathiafulvalenyl, ferrocenyl, and R-R′ = fluorenyl). Subsequent transformations involving the reactive alcohol group of some of these compounds are reported. The structures of the three title compounds have been established by single-crystal X-ray analysis.     

Unraveling the crystallization mechanism of CoAPO-5 molecular sieves under hydrothermal conditions

The hydrothermal crystallization of CoAPO-5 molecular sieves has been studied using time-resolved in-situ SAXS/WAXS, UV-vis, Raman, and XAS. Data collected during heating to 180 degrees C allowed the observation of different steps occurring during the transformation of the amorphous gel into a crystalline material from a macroscopic and atomic perspective. Raman spectroscopy detected the initial formation of Al-O-P bonds, whereas SAXS showed that these gel particles had a broad size distribution ranging from ca. 7 to 20 nm before crystallization began. WAXS showed that this crystallization was sharp and occurred at around 160 degrees C. Analysis of the crystallization kinetics suggested a one-dimensional growth process. XAS showed that Co(2+) transformed via a two-stage process during heating involving (i) a gradual transformation of octahedral coordination into tetrahedral coordination before the appearance of Bragg peaks corresponding to AFI, suggesting progressive incorporation of Co(2+) into the poorly ordered Al-O-P network up to ca. 150 degrees C, and (ii) a rapid transformation of remaining octahedral Co(2+) at the onset of crystallization. Co(2+) was observed to retard crystallization of AFI but provided valuable information regarding the synthesis process by acting as an internal probe. A three-stage, one-dimensional crystallization mechanism is proposed: (i) an initial reaction between aluminum and phosphate units forming a primary amorphous phase, (ii) progressive condensation of linear Al-O-P chains forming a poorly ordered structure separated by template molecules up to ca. 155 degrees C, and (iii) rapid internal reorganization of the aluminophosphate network leading to crystallization of the AFI crystal structure.     

The chemical synthesis of beta-(1-->4)-linked D-mannobiose and D-mannotriose

A D-cellobiose derivative was converted to D-mannobiose via simultaneous epimerization at C-2 and C-2'. Subsequent beta-D-glucosylation and epimerization at C-2" gave D-mannotriose.     

Polyfunctional compounds containing the 4,6-dialkoxy-7-arylthioheptene moiety as synthetically useful intermediates. The course of lewis acid-induced transformations

Data on the selectivity of the Lewis acids induced transformations of the title compounds are presented, and the routes leading to formation of products containing either cyclohexane or 1,3-diene units are described.     

Stereoselective association of binuclear metallacycles in coordination polymers

A series of structurally related binuclear metallacycles [Cd(NO(3))(2)L](2), where L is an angular exo-bidentate ligand, have been synthesized. Each metallacycle contains two coordinatively unsaturated, chiral metal centers within a single molecule, and the assembly of these metallacycles into polymeric framework structures has been studied systematically for the first time. Stereoselective homochiral association of [Cd(NO(3))(2)L](2) leads to the formation of helical coordination polymers, whereas meso type association results in nonhelical chain structures. The type of stereoselective aggregation depends on the conditions of self-assembly as well as on ligand functionality. Both helical and nonhelical polymeric complexes have been isolated for the metallacycle [Cd(NO(3))(2)(2,4'-pyacph)](2) (2,4'-pyacph = 2,4'-(4-ethynylphenyl)bipyridyl). Homochiral association results in the formation of helical [Cd(NO(3))]( infinity ) chains which link the binuclear [Cd(NO(3))(2)(2,4'-pyacph)](2) metallacycles into racemic two-dimensional sheets which contain both P and M [Cd(NO(3))]( infinity ) helices. In contrast, meso-association leads to the formation of nonhelical one-dimensional chains. It is shown that the product of homochiral association is predominately formed at room temperature and that of meso-association is generated at elevated temperatures. Thus, it may be concluded that the homochiral association appears to be energetically less favorable than the meso-association, a conclusion that has been confirmed by theoretical calculations of the crystal lattice energy. Several high-yield syntheses of bipyridyl-type ligands used for metallacyclic assembly are also reported.     

The Role of Binary and Many-centre Molecular Interactions in Spin Crossover in the Solid State. Part I. Equation for Free Energy

Summary. A formalism has been developed that describes spin crossover equilibrium in the solid state by taking into account the effects of n nearest neighbours of a given molecule on its partition function. In this way binary and many-body interactions of the order n + 1 are included into the theoretical model and represented by non-ideality parameters connected with the splitting of free energy levels. Binary interactions are characterised by the main splittings whereas higher order interactions manifest themselves in asymmetries of splittings within multiplets. The contribution of molecular interactions can also be written in terms of formal excess free energies of the second, third, fourth and higher orders. Simple relationships between excess free energies and parameters of multiplets have been found for binary, ternary and quaternary interactions. This formalism is reduced to that of the model of binary interactions when effects of surroundings are additive leading to equidistant free energy multiplets. Higher order interactions may cause an abrupt spin crossover but in a limited range of compositions around the transition point. The regression of experimental transition curves of one-step spin crossover may yield estimates of excess energies up to the fifth order.