Derivatives of 1,3,5-triamino-1,3,5-trideoxy-cis-inositas versatile pentadentate ligands for protein labeling with Re-186/188. Prelabeling, biodistribution, and X-ray structural studies

The pentadentate H(3)bhci [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-cis-inistol] and its bifunctionalized analogue H(3)bhci-glu-H [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-5-glutaramido-cis-inositol] were synthesized, and their coordination chemistry was investigated with inactive rhenium, with no carrier added Re-188 and with carrier added Re-186. The neutral Re(V) complexes [ReO-(bhci)] and [ReO(bhci-glu-H)] are formed in good yields starting from [ReOCl3(P(C6H5)(3))(2)] or in quantitative yield directly from [(ReO4)-Re-186/188](-) in aqueous solution by reduction with Sn(II) or Sn(0). The X-ray structures of [ReO(bhci)] and [ReO(bhci-glu-H)] were elucidated revealing pentadentate side on coordination of the ligands to the Re=O core. The basic cyclohexane frame adopts a chair form in the case of [ReO(bhci)] and a twisted boat form in the case of [ReO(bhci-glu-H)]. [ReO(bhci)] crystallizes in the monoclinic space group C2/c with a = 27.425(3), b = 14.185(1), c = 19.047(2) Angstrom, and beta = 103.64(2)degrees and [ReO(bhci-glu-H)] in the monoclinic space group P2(1)/c with a = 13.056(3), b = 10.180(1), c = 22.378(5) Angstrom and beta = 98.205(9)degrees Both Re-188 complexes are stable in human serum for at least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)](-) is readily excreted through the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLC investigations of the urine showed exclusively the complexes [ReO(bhci-glu-H)] and [ReO(bhci)], respectively, and no decomposition products. For derivatization of antibodies, the carboxylic group of [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorous reaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')(2) fragment] was labeled with [(ReO)-Re-186/188(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with full retention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibody concentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributions of Re-186-labeled intact mAb-35 as well as of its F(ab')(2) fragment in tumor-bearing nude mice revealed good uptake by the tumor with only low accumulation of radioactivity in normal tissue.

2-pyrazinylnitrene and 4-pyrimidylnitrene. Ring expansion to 1,3,5-triazacyclohepta-1,2,4,6-tetraene and ring opening to (2-isocyanovinyl)carbodiimide

Tetrazolo[1,5-a]pyrazine/2-azidopyrazine 9T/9A undergo photolysis in Ar matrix at cryogenic temperatures to yield 1,3,5-triazacyclohepta-1,2,4,6-tetraene 21 as the first observable intermediate, and 1-cyanoimidazole 11 and (2-isocyanovinyl)carbodiimide 22 as the final products. The latter tautomerizes to 2-(isocyanovinyl)cyanamide 23 on warming to 40 K. The same intermediate 21 and the same final products are obtained on matrix photolysis of the isomeric tetrazolo[1,5-c]pyrimidine/4-azidopyrimidine 24T/24A. These photolysis results as well as those of the previously reported thermal ring contraction of N-15-labeled 2-pyrazinyl- and 4-pyrimidylnitrenes to 1-cyanoimidazoles can all be rationalized in terms of selective ring opening of 21 or nitrine 10 to a nitrile ylide zwitterion 28 prior to formation of the final products, 11 and 22. The results are supported by high-level ab initio and DFT calculations (CASPT2-CASSCF(6,6), G3(MP2), and B3LYP/6-31+G*) of the energies and IR spectra of the intermediates and products.

Synthesis of novel 2-amino-1,3-thiazole-5-carboxylates utilising ultrasonic and thermally mediated aminolysis

Novel 2-amino-1,3-thiazole-5-carboxylates have been synthesised in high yield by unprecedented ultrasonic and thermally mediated nucleophilic displacement of bromide from ethyl 2-bromo-1,3-thiazole-5-carboxylate by primary, secondary and aryl amines.

3,5-cycle decompositions

For all odd integers n and all non-negative integers r and s satisfying 3r + 5s = n(n -1)/2 it is shown that the edge set of the complete graph on n vertices can be partitioned into r 3-cycles and s 5-cycles. For all even integers n and all non-negative integers r and s satisfying 3r + 5s = n(n-2)/2 it is shown that the edge set of the complete graph on n vertices with a 1-factor removed can be partitioned into r 3-cycles and s 5-cycles. (C) 1998 John Wiley & Sons, Inc.

The 2.0 angstrom crystal structure of a pocilloporin at pH 3.5: The structural basis for the linkage between color transition and halide binding

The pocilloporin Rtms5 and an engineered variant Rtms5(H146S) undergo distinct color transitions (from blue to red to yellow to colorless) in a pH-dependent manner. pK(a) values of 4.1 and 3.2 were determined for the blue (absorption lambda(max), 590 nm) to yellow (absorption lambda(max), similar to 453 nm) transitions of Rtms5 and Rtms5H(146). The pK(a) for the blue-yellow transition of Rtms5H(146S) increased by 1.4 U in the presence of 0.1 M KI, whereas the pK(a) for the same transition of Rtms5 was relatively insensitive to added halides. To understand the structural basis for these observations, we have determined to 2.0 A resolution the crystal structure of a yellow form of Rtms5(H146S) at pH 3.5 in the presence of iodide. Iodide was found occupying a pocket in the structure with a pH of 3.5, forming van der Waals contacts with the tyrosyl moiety of the chromophore. Elsewhere, it was determined that this pocket is occupied by a water molecule in the Rtms5(H141S) structure (pH 8.0) and by the side chain of histidine 146 in the wild-type Rtms5 structure. Collectively, our data provide an explanation for the observed linkage between color transitions for Rtms5(H146S) and binding to halides.

1H-1,3-Diazepines, 5H-1,3-diazepines, 1,3-diazepinones, and 2,4-diazabicyclo[3.2.0]heptenes

Tetrazolo[1,5-a] pyridines/ 2-azidopyridines 1 undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 3, which react with alcohols to afford 2-alkoxy-1H-1,3-diazepines 4 (5), with secondary amines to 2-dialkylamino-5H-1,3-diazepines 16, sometimes via isolable 2-dialkylamino-1H-1,3-diazepines 15, and with water to 1,3-diazepin-2-ones 19. The latter are also obtained by elimination of isobutene or propene from 2-tert-butoxy- or 2-isopropoxy-1H-1,3-diazepines 4 or 5. 1,3-Diazepin-2-one 22B and 1,3-diazepin-4-one 24 were obtained from hydrolysis of the corresponding 4-chlorodiazepines. Diazepinones 19 undergo photochemical ring closure to diazabicycloheptenones 25 in high yields. The 2-alkoxy-1H-1,3-diazepines 4 and 5 interconvert by rapid proton exchange between positions N1 and N3. The free energies of activation for the proton exchange were measured by the Forsen - Hoffman method as DeltaGdouble dagger(298) = 16.2 +/- 0.6 kcal mol(-1) as an average for 4a - c in CD2Cl2, acetone-d(6), and methanol-d(4), and 14.1 +/- 0.6 kcal mol(-1) for 4c in acetone/D2O. The structures of 2-methoxy-5,6-bis( trifluoromethyl)-1H-1,3-diazepine 4k, 1,2-dihydro-4-diethylamino-5H-1,3-diazepin-2-one 22bB, and diazabicycloheptanone 26 were determined by X-ray crystallography. The former represents the first reported X-ray crystal structure of any monocyclic N-unsubstituted 1H-azepine.

Synthesis of 1,3-diazepines and ring contraction to cyanopyrroles

Several tetrazolo[1,5-a] pyridines/2-azidopyridines undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes (7,10,13,16,19,22) as well as ring cleavage to cyanovinylketenimines (8,17,20b) in low temperature Ar matrices. 6,8-Dichlorotetrazolo[1,5-a] pyridine/2-azido-3,5-dichloropridine 6 undergoes ready exchange of the chlorine in position 8 (3) with ROH/RONa. 8-Chloro-6-trifluoromethyltetrazolo[1,5-a] pyridine 15 undergoes solvolysis of the CF3 group to afford 8-chloro-6-methoxycarbonyltetrazolo[1,5-a] pyridine 18. Several tetrazolopyridines/2-azidopyridines afford 1H- or 5H-1,3-diazepines in good yields on photolysis in the presence of alcohols or amines (11,14,23,25). 5-Chlorotetrazolo[1,5-a] pyridines/2-azido-6-chloropyridines 21 and 38 undergo a rearrangement to 1H- and 3H-3-cyanopyrroles 27 and 45, respectively. The mechanism of this rearrangement was investigated by N-15-labelling and takes place via transient 1,3-diazepines. The structures of 6,8-dichloro-tetrazolo[1,5-a] pyridine 6T, 6-chloro-8-ethoxytetrazolo[1,5-a] pyridine 9Tb, dipyrrolylmethane 28, and 2-isopropoxy-4-dimethylamino-5H-1,3-diazepine 25b were determined by X-ray crystallography. In the latter case, this represents the first reported X-ray crystal structure of a 5H-1,3-diazepine.

Facile ketene-ketene and ketene-ketenimine rearrangements: A study of the 1,3-migration of alpha-substituents interconverting alpha-imidoylketenes and alpha-oxoketenimines, a pseudopericyclic reaction

Theoretical calculations (B3LYP/6-311+G(3df,2p)//B3LYP/6-31G*) of the 1,3 migration of NR2 transforming alpha-oxoketenimines 1 to alpha-imidoylketenes 3 and vice versa indicate that this process is a pseudo-pericyclic reaction with a low activation energy (NH2 97 kJ mol(-1), N(CH3)(2) 62 kJ mol(-1)). The oxoketenimines were found to be more stable (by 18-35 kJ mol(-1)) which is in line with experimental observations. The hindered amine rotation in the amide and amidine moieties adjacent to the cumulenes are important in the migration of the NR2 group, as one of the rotation transition states is close to the 1,3 migration pathway. This gives an interesting potential energy surface with a valley-ridge inflection (VRI) between the orthogonal hindered amine rotation and 1,3 migration transition states. The imidoylketene may also undergo ring closure to an azetinone 5; however, this is metastable, and under the conditions that allow the 1,3-migration, the oxoketenimine 1 will be favored. The imine NH E/Z-interconversion of the ketenimine group takes place by inversion and has a low activation barrier (similar to40 kJ mol(-1)). In all the amidines examined the E/Z-interconversion of the imine function was predicted to be by rotation with a high barrier (>80 kJ mol(-1)), in contrast to all other reported imine E/Z-interconversions which are by inversion.

Oxoketene-oxoketene, imidoylketene-imidoylketene and oxoketenimine-imidoylketene rearrangements. 1,3-shifts of phenyl groups

Dibenzoylketene 5 undergoes degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms, thus interconverting it with 6 and 7. This 1,3-shift takes place in the gas phase under flash vacuum thermolysis (FVT) conditions, but not in solution at 110-145 degrees C. Imidoyl(benzoyl)ketene 13 undergoes degenerate 1,3-shift of the phenyl group on FVT, thus interconverting it with 14, but the ketenimine isomer 15 is not formed, and none of these shifts take place in the solid state at 250 degrees C. Imidoyl(p-toluoyl)ketene 21 undergoes a 1,3-p-tolyl shift, interconverting it with ketene 22 but not with ketenimine 23. The imidoyl(p-toluoyl)ketene rotamer 25 cyclizes to 4-toluoyloxyquinoline 28 and 4-quinolone 29. The cyclization of imidoyl(benzoyl)ketene 13 to 4-benzoyloxyquinoline 18, and of 25 to 28 involves 1,3-C-to-O shifts of benzoyl (toluoyl) groups. Calculations of the transition states for the transformations at the B3LYP/6-31G** level of theory are in agreement with the observed reaction preferences.

XSophe-Sophe-XeprView (R). A computer simulation software suite (v. 1.1.3) for the analysis of continuous wave EPR spectra

The XSophe-Sophe-XeprView((R)) computer simulation software suite enables scientists to easily determine spin Hamiltonian parameters from isotropic, randomly oriented and single crystal continuous wave electron paramagnetic resonance (CW EPR) spectra from radicals and isolated paramagnetic metal ion centers or clusters found in metalloproteins, chemical systems and materials science. XSophe provides an X-windows graphical user interface to the Sophe programme and allows: creation of multiple input files, local and remote execution of Sophe, the display of sophelog (output from Sophe) and input parameters/files. Sophe is a sophisticated computer simulation software programme employing a number of innovative technologies including; the Sydney OPera HousE (SOPHE) partition and interpolation schemes, a field segmentation algorithm, the mosaic misorientation linewidth model, parallelization and spectral optimisation. In conjunction with the SOPHE partition scheme and the field segmentation algorithm, the SOPHE interpolation scheme and the mosaic misorientation linewidth model greatly increase the speed of simulations for most spin systems. Employing brute force matrix diagonalization in the simulation of an EPR spectrum from a high spin Cr(III) complex with the spin Hamiltonian parameters g(e) = 2.00, D = 0.10 cm(-1), E/D = 0.25, A(x) = 120.0, A(y) = 120.0, A(z) = 240.0 x 10(-4) cm(-1) requires a SOPHE grid size of N = 400 (to produce a good signal to noise ratio) and takes 229.47 s. In contrast the use of either the SOPHE interpolation scheme or the mosaic misorientation linewidth model requires a SOPHE grid size of only N = 18 and takes 44.08 and 0.79 s, respectively. Results from Sophe are transferred via the Common Object Request Broker Architecture (CORBA) to XSophe and subsequently to XeprView((R)) where the simulated CW EPR spectra (1D and 2D) can be compared to the experimental spectra. Energy level diagrams, transition roadmaps and transition surfaces aid the interpretation of complicated randomly oriented CW EPR spectra and can be viewed with a web browser and an OpenInventor scene graph viewer.

User guide for shock and blast simulation with the OctVCE code (version 3.5+), Department of Mechanical Engineering Report 2007/13

OctVCE is a cartesian cell CFD code produced especially for numerical simulations of shock and blast wave interactions with complex geometries. Virtual Cell Embedding (VCE) was chosen as its cartesian cell kernel as it is simple to code and sufficient for practical engineering design problems. This also makes the code much more ‘user-friendly’ than structured grid approaches as the gridding process is done automatically. The CFD methodology relies on a finite-volume formulation of the unsteady Euler equations and is solved using a standard explicit Godonov (MUSCL) scheme. Both octree-based adaptive mesh refinement and shared-memory parallel processing capability have also been incorporated. For further details on the theory behind the code, see the companion report 2007/12.

On the structure, electrochemistry, and spectroscopy of the (N,N'-bis(2'-(dimethylamino)ethyl)-N,N'-dimethylpropane-1,3-diamine)copper(II) ion

The synthesis, spectroscopy, and electrochemistry of the acyclic tertiary tetraamine copper(II) complex [CuL(1)](ClO4)(2) (L(1) = N,N-bis(2'-(dimethylamino)ethyl)-N,N'-dimethylpropane-1,3-diamine) is reported. The X-ray crystal structure of [CuL(1)(OClO3)(2)] reveals a tetragonally elongated CuN4O2 coordination sphere, exhibiting relatively long Cu-N bond lengths for a Cu-II tetraamine, and a small tetrahedral distortion of the CuN4 plane. The [CuL(1)](2+) ion displays a single, reversible, one-electron reduction at -0.06 V vs Ag/AgCl. The results presented herein illustrate the inherent difficulties associated with the separation and characterization of Cu-II complexes of tertiary tetraamines, and some previously incorrect assertions and unexplained observations of other workers are discussed.