Alternative syntheses of the D2d symmetric 1,3,5,7-tetraiodotricyclo[3.3.0.0]octane

Three alternative syntheses of 1,3,5,7-tetraiodotricyclo[3.3.0.0^3,7]octane are described. Reaction of this tetraiodide with sodium amalgam in the presence of dienes or with molten sodium in boiling 1,4-dioxane in the absence of trapping agents led to very complex mixtures of products, presumably due to competitive 1,2- and 1,3-deiodination reactions.     

Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction

SU11248 is a potent inhibitor of PDGFR, VEGFR, KIT, and Flt3, and is currently under Phase I clinical evaluation as an anticancer drug. A sensitive and specific analytical method for the quantitation of SU11248 and its metabolite in several monkey tissues (liver, kidney, brain and white fat) using LC-MS-MS following semi-automated liquid-liquid extraction (LLE) was developed and validated. Amounts of 50 mg of tissue were homogenized using an ultrasonic processor. After addition of the stable labelled internal standard (IS) and ammonium hydroxide (0.3%), samples were extracted with 2.5 ml of tert-butyl methyl ether. Following centrifugation, aliquots of 1.8 ml of the organic phase were transferred into a 96-well plate. The Packard Multiprobe II robotic liquid handler was used to perform all steps mentioned above. The organic phase was dried and the residue was reconstituted with 800 microl of 15 mM ammonium formate buffer solution (pH 3.25) using a Tomtec Quadra 96 workstation. Aliquots of 10 microl of the resulting solution were injected into the LC-MS-MS system. A Symmetry Shield C8 column (50 mm x 2.1 mm, 3.5 microm) was used to perform the chromatographic analysis. The mobile phase was 15 mM ammonium formate buffer solution (pH 3.25)-acetonitrile (74:26 (v/v)) with a flow-rate of 0.35 ml/min. Retention times of the metabolite and SU11248 were about 2.5 and 3.5 min, respectively. Total cycle time was 5 min. MS detection used the Applied Biosystems-MDS Sciex API 3000 with TurbolonSpray interface and multiple reaction monitoring (MRM) operated in positive ion mode. The method was validated for both compounds over the calibration range of about 2 and 2000 ng/g. The suitability and robustness of the method for in vivo samples were confirmed by analysis of monkey tissues from animals dosed with SU11248.     

Interaction of l-malic acid with alkaline metals and open chain polyammonium cations in aqueous solution

This work reports a potentiometric, calorimetric and spectropolarimetric ultraviolet circular dichroism (UV/CD) study of the interaction of l-malic acid with alkaline metals or (poly)ammonium (methylamine, ethylenediamine, diethylenetriamine, triethylenetetramine, spermine, tetraethylenepentamine and pentaethylenehexamine) cations. Stability data (logK, DeltaG(0)) were obtained potentiometrically for the l-malic acid with (poly)ammonium cations systems; calorimetric measurements (25 degrees C) made it possible to obtain DeltaH(0) and TDeltaS(0) values for the complexes formed in the systems under examination. logK values calculated (for the reaction: H(i)A(i+)+H(j)L((j-z))=ALH(r)((i+j-z)), with r=i+j) range between 0.8 and 4.6, i.e., the interactions are from weak to fairly strong while maximum stability for each system is given by the species with the highest z(anion)xz(cation) (z=charge) value. Enthalpy changes associated with reactions H(n)A(n+)+L(2-)=ALH(n)((n-2)) and H(n)A(n+)+HL(-)=ALH(n+1)((n-1)) are always positive and increase progressively with n. The same is valid for T DeltaS(0) values, which indicate that these species are entropically stabilized, as expected for electrostatic interactions. It was verified that the UV/CD signal depends on both ionic medium and ionic strength value; for comparison, we used the l-malic acid signal recorded in tetramethylammonium chloride as baseline background salt (as in potentiometry). UV/CD spectra were recorded for solutions containing both cationic and anionic species. When the cation was a protonated polyamine, CD spectra calculations were performed for most stable ion pairs: the results show remarkable differences in Deltaepsilon (dm(3) mol(-1) cm(-1)) values at 205 nm (which is the l-malate UV/CD lambda(max)) between the chiral ligand and its complex with a polyamine.     

Stable σ-adducts of 4,6-dinitrotetrazolo[1,5-a]pyridine with alkoxide anions

The reaction of 2-chloro-3,5-dinitropyridine with two equivalents of KN₃ in the presence of ROH results in stable Meisenheimer-type -adducts of 4,6-dinitrotetra-zolo[1,5-a]pyridine with RO^– anions (R = H, Alk, Ph). The mechanism of -complex formation was suggested. The structure of the -adduct with R = Me was established by IR and NMR spectroscopy and by X-ray diffraction analysis.For the preliminary communication, see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1278–1283, July, 1994.This work was supported by the Russian Foundation for Basic Research (project code 93-03-5329).     

Formation and stability of pyrophosphate complexes with aliphatic amines in aqueous solution

The complex formation between pyrophosphate (P(2)O(7)(4-)) and protonated methylamine, ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine and pentaethylenehexamine, has been studied potentiometrically, in aqueous solution, at 25 degrees C. It was found that the species ALH(q)(A = amine, L = P(2)O(7)(4-)) are formed with q = 1 ... n(n = 3, 5, 6, 7, 7 and 8 for the above amines respectively). Mono- and di-amines form species A(p)LH(q) too. The stability of these species is quite high [e.g. H(4)A(4+) + HL(3-)ALH(5)(+): log K = 8.1 (A = pentaethylenehexamine)] and depends strictly on the charges involved in the formation reaction. Charges of reactants being equal, the stability trend is penten > tetren > trien > dien > en > meta and cationic mixed species are more stable than anionic ones. These results are discussed in relation to speciation problems in natural and biological fluids.     

Monitoring of the metal displacement from the recombinant mouse liver metallothionein Zn(7)-complex by capillary zone electrophoresis with electrospray MS detection

A solution of a Zn-complex of recombinant mouse MT-1 isoform (Zn(7)-MT-1) was prepared and titrated with Cd(2+) ions. A method based on the coupling of capillary zone electrophoresis (CZE) with electrospray MS detection was developed for the analysis of the stoichiometry of the species formed during the titration. The method offered the possibility of the on-line removal of up to 100 mM Tris or phosphate buffer solutions that would otherwise suppress the electrospray signal. By allowing the determination of the metal stoichiometry of the complex species present in solution the method was shown to be complementary to circular dichroism and UV-VIS spectrophotometry conventionally used for similar studies. The titration of the Zn(7)-MT complex with Cd(II) showed the sequential displacement of the Zn by Cd. The unusually high stability of the Cd(6)Zn(1)-MT species was observed which suggests a structural role of the remaining Zn(II) ion.     

Synthesis of microcin SF608

The first total synthesis of aquatic peptide microcin SF608 is described. Coupling of L-Hpla with the dipeptide L-Phe-L-Choi followed by coupling with agmatine and a deprotection step gave microcin SF608. In addition, the levorotatory character of L-Hpla (5) was thoroughly established, and the conformational analysis of L-Choi containing peptides 1 and 8-10 was performed using NMR spectroscopy to examine the cis-trans isomer equilibrium of the L-Phe-L-Choi amide bond.     

New synthetic approach to enantiopure bicyclic sulfonium salts: swainsonine analogues

The enantioselective synthesis of bicyclic sulfonium salts 8 or 9, thioanalogues of swainsonine derivatives, is described. The synthetic strategy is based on a stereo- and regiospecific transannular cyclization reaction of nine-membered cyclic sulfides, mediated by Me(3)SiI or carried out under acidic catalysis.