A spiro-linked pyrene-naphthoquinone.

The title molecule, 2'-pyrenylspiro[2, 3-dihydro-1H-cyclopenta[b]naphthalene-2,5'-1',3'-dioxane]-4,9-dione, C(32)H(22)O(4), contains an electron-donating pyrene group spiro-linked to an electron-accepting naphthoquinone. The molecules are V-shaped in profile and stack to form columns along b with alternating, approximately coplanar, pyrene and naphthoquinone fragments. Intermolecular contacts within a column are consistent with some degree of pi contact and possible long-range delocalization. Individual columns form a herringbone pattern when the crystal is viewed along b.

Aminohexanoic hydroxamate is a potent inducer of the differentiation of mouse neuroblastoma cells.

Deoxyhypusine synthase is the key enzyme for modifying a lysine residue to hypusine in the cellular protein eukaryotic initiation factor 5A (eIF-5A). Deletion of the deoxyhypusine synthase or the eIF-5A gene in yeast produces lethal phenotype. Inhibition of deoxyhypusine synthase by 1-guanidino-7-aminoheptane (GC7) suppresses tumor cell growth. Hypusine formation represents one of the most specific polyamine-dependent biochemical reactions. In view of the importance of polyamines in growth regulation and cancer biology, deoxyhypusine synthase has been considered to be a good target for chemotherapeutic drug design. Using GC7 as a prototype we have synthesized and tested three classes of diamine analogs, namely, guanidino-, pyrimidino-, and hydroxamate derivatives, as potential inhibitors for deoxyhypusine synthase. Our study shows that (i) among all the compounds tested, GC7 remained to be the most potent inhibitor for deoxyhypusine synthase; (ii) N,N'-bispyrimidino-1, 9-diaminononane, although a poor inhibitor of deoxyhypusine synthase, was a potent growth inhibitor; and (iii) one of the hydroxamate derivatives, 6-aminohexanoic hydroxamate (HC6), prominently induced the differentiation of mouse neuroblastoma cells at sub-millimolar concentrations. Interestingly, other hydroxamates with different chain length were not nearly as effective as HC6 in inducing neuroblastoma cell differentiation. The effect of HC6 was also unique in that it could induce neurite outgrowth and the expression of neuron-specific genes such as synapsin I and MAP-2 in neuroblastoma cells in the absence of other promoting agents such as cAMP. The effect of HC6 on neuroblastoma cell differentiation was comparable with, or better than that of N(6),O(2)'-dibutyryl cAMP (Bt(2)cAMP), a standard reagent commonly used for inducing the differentiation of mouse and human neuroblastoma cells in culture.

Copper(II) and nickel(II) complexes of binucleating macrocyclic bis(disulfide)tetramine ligands.

Novel macrocyclic bis(disulfide)tetramine ligands and several Cu(II) and Ni(II) complexes of them with additional ligands have been synthesized by the oxidative coupling of linear tetradentate N2S2 tetramines with iodine. Facile demetalation of the Ni(II) oxidation products affords the free 20-membered macrocycles meso-9 and rac-9 and the 22-membered macrocycle 16, all of which are potentially octadentate N4S4 ligands. X-ray structure analyses reveal distinctly different conformations for the two isomers of 9; meso-9 shows a stepped conformation in profile with the disulfide groups corresponding to the rise of the step, whereas rac-9 exhibits a V conformation with the disulfide groups near the vertex of the V. No metal complexes of rac-9 have been isolated. Crystallographic studies of three Cu(II) complexes reveal that depending upon the size of the macrocyclic ligand and the nature of the additional ligands (I-, NCO-, and CH3CN), the Cu(II) coordination geometry shows considerable variation (plasticity), with substantial changes in the Cu(II)-disulfide bonding. Thus, a diiodide salt contains six-coordinate Cu(II) to which all four bridging disulfide sulfur atoms form strong equatorial bonds. In contrast, isocyanato complexes of the 20- and 22-membered macrocycles exhibit trigonal-bipyramidal Cu(II) and distorted cis-octahedral Cu(II) geometries, respectively, having only one and no short equatorially bound sulfur atoms. The coordination geometry of the latter complex can also be described as four-coordinate seesaw with two semicoordinated S(disulfide) ligands. Disulfide-->Cu(II) ligand-to-metal charge transfer absorptions of both isocyanato-containing Cu(II) species appear too weak to observe, probably because of poor overlap of the sulfur orbitals with the Cu(II) d-vacancy. The dual disulfide-bridged Ni(II) units of the crystallographically characterized octahedral Ni(II) complex of meso-9 with axial iodide and acetonitrile ligands promote substantial antiferromagnetic coupling (J = -13.0(2) cm-1).

A mixed-metal pentanuclear complex containing linked NiIIN2S2 and CuII units.

Bis[(1S,2S)-trans-3,3'-(1,2-cyclohexanediyldinitrilo)bis- (2-methylpropane-2-thiolato)]-1 kappa 4N1,N1',S1,S1';2 kappa 4N2,- N2',S2,S2';3 kappa 2S1,S2';4 kappa 2S1',S2;5 kappa 2S1',S2'-triiodo-3 kappa I, 4 kappa I,- 5 kappa I-tricopper(I)dinicke1(II) bis(acetonitrile) solvate, [[Ni(C14H28N2S2)]2(CuI)3]. 2CH3CN, is one of a number of possible novel pentanuclear complexes formed from MIIN2S2 units with available donating thiolate ligands. In the title compound, three CuII groups bridge thiolate ligands from two approximately square-planar [NiIIN(amine)2S(thiolate)2] units to form the pentanuclear complex. The coordination geometry of each Cu atom is approximately trigonal planar.

Effects of inhibitors of deoxyhypusine synthase on the differentiation of mouse neuroblastoma and erythroleukemia cells.

Deoxyhpusine synthase catalyzes the conversion of lysine to deoxyhypusine residue on the eukaryotic initiation factor 5A (eIF-5A) precursor using spermidine as the substrate. Subsequent hydroxylation of the deoxyhypusine residue completes hypusine formation on eIF-5A. Polyamines (putrescine, spermidine, and spermine) have been implicated in tumor growth and differentiation. Because deoxyhypusine/hypusine formation is one of the most specific polyamine-dependent biochemical events, we decided to use N1-guanyl-1,7-diaminoheptane (GC7), a potent inhibitor for deoxyhypusine synthase, to assess the role of hypusine formation on tumor growth and differentiation. GC7 suppressed the growth of N2a mouse neuroblastoma cells and DS19 murine erythroleukemia cells at micromolar concentrations. However, within a narrow concentration range, GC7 could promote the differentiation of mouse neuroblastoma cells in the presence of suboptimal amount of dibutyryl cAMP. In contrast, GC7 blocked the differentiation of DS19 cells induced with hexamethylene bisacetamide. Polyamine depletion by difluoromethyl ornithine (DFMO) has previously been shown to promote differentiation of neuroblastoma cells but inhibits erythrodifferentiation. Since our studies demonstrated that GC7 mimics the action of DFMO on tumor differentiation, it is likely that the effect of DFMO on tumor differentiation is mediated by hypusine formation and that GC7 represents a more specific inhibitor that can alter the differentiation program in certain tumor cells.

Tris(3,5-dimethylpyrazol-1-yl)methylsilane.

The structure consists of discrete molecules of tris-(3,5-dimethylpyrazol-1-yl)methylsilane, C16H24N6Si, that exhibit distorted tetrahedral SiN(pyrazole)3C geometry about the Si atom. The Si and methyl C atoms lie on threefold axes. The C--Si--N and N--Si--N bond angles are 111.3 (2) and 107.5 (2) degrees, respectively, while the Si--N bond length is 1.745 (5) A. The present work provides the first reported structure containing an Si--N(pyrazole) linkage.

Isostructural trigonal-bipyramidal CuII and nominally 1% CuII-doped ZnII complexes with N5 ligation.

[Cu(C6H18N4)(C10H10N2)](ClO4)2, (1-benzylimidazole)[N,N-bis(2-aminoethyl)-1,2-ethanediamine]copper(II) diperchlorate (1), M(r) = 566.88, monoclinic, P2(1)/c, a = 10.549 (1), b = 9.2465 (9), c = 25.256 (2) A, beta = 101.42 (1) degrees, V = 2415 (1) A3, Z = 4, Dm = 1.54 (1), Dx = 1.559 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 1.18 mm-1, F(000) = 1172, T = 296 (1) K, R = 0.048, wR = 0.069 for 3063 reflections. [Zn0.99Cu0.01(C6H18N4)(C10H10N2)](ClO4)2, 1% CuII-doped (1-benzylimidazole)[N,N-bis(2-aminoethyl)-1,2-ethanediamine]zinc(II) diperchlorate (2), M(r) = 568.72, monoclinic, P2(1)/c, a = 10.708 (1), b = 9.229 (2), c = 25.205 (2) A, beta = 101.867 (8) degrees, V = 2438 (1) A3, Z = 4, Dm = 1.54 (1), Dx = 1.549, lambda (Mo K alpha) = 0.71073 A, mu = 1.30 mm-1, F(000) = 1176, T = 295 (1) K, R = 0.041, wR = 0.055 for 3282 reflections. The isostructural distorted trigonalbipyramidal MN5 cations are separated by perchlorate anions. Equatorial M--N distances are similar in both cations [range 2.083 (3) to 2.105 (3) A for (1); 2.073 (3) to 2.084 (3) A for (2)]. In contrast, the axial M--N distances differ substantially [2.043 (3) and 1.971 (3) A for (1); 2.255 (4) and 2.054 (3) A for (2)]. Axial contraction in the copper complex (1) is consistent with a dz2 ground state.

Structure of pentaamminechlororuthenium(III) bisulfate tetrahydrate.

[RuCl(NH3)5](HSO4)2.4H2O, M(r) = 487.88, triclinic, P1, a = 10.0422 (5), b = 14.1044 (7), c = 6.3273 (6) A, alpha = 100.369 (5), beta = 98.655 (6), gamma = 81.354 (4) degree, V = 864.5 (3) A3, Z = 2, Dm = 1.86 (1), D chi = 1.874 g cm-3, lambda(MO K alpha) = 0.71073 A, mu = 13.3 cm-1, F(000) = 498, T = 296 (1) K, R = 0.025 for 4622 unique reflections with I greater than 3 sigma(I). The structure contains (NH3)5RuCl2+ cations, bisulfate anions and solvate water molecules all linked by an extensive hydrogen-bonding network. Each Ru ion is coordinated in a distorted octahedral fashion by five ammonia molecules and a chloride ion. The Ru--Cl distance [2.3742 (5) A] is typical for RuIII--Cl linkages. The Ru--NH3 distances span a narrow range [2.096 (2)-2.119 (2) A] and provide no evidence for a trans effect.

Structures of zinc(II) with tetradentate N2S2 ligation.

trans-3,3'-(1,2-Cyclohexanediyldinitrilo)-bis(2-methylpropane++ +-2-thiolato )]zinc(II), [Zn(C14H28-N2S2)], Zn(2), Mr = 353.89, monoclinic, C2/c, a = 17.914 (4), b = 9.440 (1), c = 10.877 (2) A, beta = 110.19 (2)degrees, V = 1726 (1) A3, Z = 4, Dm = 1.35 (1), Dx = 1.360 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 0.17 mm-1, F(000) = 752, T = 298 (1) K, RF = 0.026, wRF = 0.037 for 1290 reflections. 3,3'-(1,2-Cyclohexa-1,4- dienediyldinitrilo)bis(2-methylpropane-2-thiolato)] zin c(II), [Zn(C14H24N2S2)], Zn(3), Mr = 349.86, monoclinic, P2(1)/c, a = 9.760 (2), b = 17.326 (3), c = 10.530 (2) A, beta 91.49 (2)degrees, V = 1780 (1) A3, Z = 4, Dm = 1.31 (1), Dx = 1.305 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 0.16 mm-1, F(000) = 736, T = 297 (1) K, RF = 0.050, wRF = 0.062 for 1723 reflections. The structures consist of discrete complexes with distorted-tetrahedral ZnS2(thiolate)N2(amine) coordination geometries. Zn--S [2.2533 (6) A for Zn(2); 2.259 (1), 2.253 (1) A for Zn(3)] and Zn--N [2.101 (2) A for Zn(2); 2.088 (4), 2.128 (4) A for Zn(3)] distances are close to those reported for similar structures with bidentate N(amine)S(thiolate) ligands. The N,S chelate rings in both structures exhibit the envelope conformation with the tetrasubstituted C atoms comprising the flaps. In Zn(3), the central N,N chelate ring adopts the envelope conformation, while in Zn(2), the corresponding ring is gauche.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure of 1% copper(II)-doped dichlorobis(1,2-dimethylimidazole)zinc(II).

[Zn0.99Cu0.01Cl2(C5H8N2)2], Mr = 328.43, monoclinic, P2(1)/c, a = 13.587 (1), b = 7.1324 (7), c = 16.356 (2) A, beta = 112.87 (1) degrees, V = 1460.4 (5) A3, Z = 4, Dm = 1.50 (1), Dx = 1.492 g cm-3, mu(Mo K alpha, lambda = 0.71073 A) = 20.8 cm-1, F(000) = 672.0, T = 297 (1) K, R = 0.028 for 1782 unique observed reflections. The structure contains discrete dichlorobis(1,2-dimethylimidazole)zinc(II) molecules. Pseudotetrahedral N2Cl2 coordination about zinc is effected by coordination to two imidazole and two chloride ligands. The Zn-N [2.006 (3), 2.008 (3) A] and Zn-Cl [2.2509 (8), 2.2468 (8) A] distances lie within +/- 0.01 A of those in the structurally similar compound [ZnCl2(imidazole)2]. Angles within the coordination sphere L-Zn-L' range from 105.39 (7) to 115.37 (8) degrees. The N-Zn-N angle [115.37 (8) degrees] is 5-10 degrees larger than those for several [ZnL2Cl2] complexes where L is imidazole, 4-substituted pyridine or 3,5-dimethylpyrazole.

Structures of a spiro[3.3]heptane and a related dispiro[3.1.3.1]decane derivtive.

2,2,6,6-Tetrakis(mesyloxymethyl)spiro[3.3]heptane (1), C15H28O12S4, Mr = 528.64, triclinic, P1, a = 10.319 (1), b = 14.233 (2), c = 8.5187 (9) A, alpha = 97.87 (1), beta = 104.08 (1), gamma = 98.86 (1) degrees, V = 1179.0 (6) A3, Z = 2, Dm = 1.46 (1), Dx = 1.489 Mg m-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.44 mm-1, F(000) = 556, T = 298 (1) K, R = 0.036 for 2411 reflections. Diethyl 8,8-bis(mesyloxymethyl)dispiro[3.1.3.1]decane-2,2-dicarboxyl ate (2) C20H32O10S2, Mr = 496.60, triclinic, P1, a = 12.168 (1), b = 16.789 (2), c = 5.9411 (6) A, alpha = 90.416 (8), beta = 94.294 (9), gamma = 87.590 (9) degrees, V = 1209.2 (4) A3, Z = 2, Dm = 1.35 (1), Dx = 1.364 Mg m-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.26 mm-1, F(000) = 528, T = 292 (1) K, R = 0.037 for 2530 reflections. The cyclobutane rings in both structures are puckered. Dihedral angles of these rings in the spiroheptane derivative (1) [12.9 (7) and 21.2 (5) degrees], and in the end rings of the dispirodecane derivative (2) [18.9 (5) and -18.5 (4) degrees], are significantly smaller than that for the central cyclobutane ring in (2) [29.0 (3) degrees]. Ring puckering in (2) gives the molecule a decided bow shape when viewed normal to the best plane of the central four-membered ring.

A charge-transfer complex of benzene with a highly twisted perylene derivative.

2C6H6.C26H6Cl8N2O4, benzene-1,2,5,6,7,8-11,12-octachloro-N,N'-dimethylperylene-3 ,4:9,10-bis- (dicarboximide) (Cl8DMP) (2/1), Mr = 850.20, orthorhombic, Pna2(1), a = 23.076 (2), b = 7.2492 (6), c = 20.277 (2) A, V = 3392.0 (8) A3, Z = 4, Dm = 1.69 (1), Dx = 1.665 g cm-3, mu (Mo K alpha, lambda = 0.71073 A) = 7.1 cm-1, F(000) = 1712, T = 297 (1) K, RF = 0.061 for 2134 observed reflections. The structure contains alternating benzene and Cl8DMP molecules stacked along b to form a 2:1 donor-acceptor complex. The Cl8DMP molecule is highly twisted as a result of short intramolecular bay Cl...Cl contacts [3.109 (3), 3.136 (3) A]. The central ring of the perylene fragment is substantially distorted from planarity; internal torsion angles range from 16 (1) to 32 (1) degrees.

Structures of tetrakis(1,2-dimethylimidazole)MII diperchlorates (MII = Ni,Cu).

[Ni(C5H8N2)4]2+.2ClO4-, Mr = 642.14, monoclinic, P2(1)/n, a = 17.938 (2), b = 14.438 (2), c = 11.336 (2) A, beta = 93.38 (1) degrees, V = 2931 (1) A3, Z = 4, Dm = 1.44 (1), D chi = 1.455 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 0.90 mm-1, F(000) = 1336, T = 297 (1) K, RF = 0.061, wRF = 0.076 for 2676 reflections. [Cu(C5H8N2)4]2+.2ClO4-, Mr = 646.97, monoclinic, P2(1)/n, a = 98.413 (7) degrees, V = 2873 (1) A3, Z = 4, Dm = 1.47 (1), D chi = 1.496 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 1.00 mm-1, F(000) = 1340, T = 297 (1) K, RF = 0.053, wRF = 0.069 for 2889 reflections. Three of the four ClO4 groups in both structures showed disorder; they were modeled as single-site Cl atoms with unrestrained low-occupancy O atoms. Each NiII ion is coordinated in a distorted square-planar fashion by four N donor atoms from the dimethylimidazole groups. The Ni-N distances are typical. In the Cu complex, one ligand showed an approximate twofold disorder about the Cu-N(im) direction. Each CuII ion also has four square-planar equatorial Cu-N(im) bonds and, in addition, shows unusually weak axial coordination by two O(ClO4) atoms. The Cu-O(ClO4) distances are substantially longer than those found for typical tetragonal CuN4O2(ClO4) coordination, and the observed Cu-O-Cl angles are much larger than usual.

Structure of a novel, macrocyclic Schiff base.

(E,E)-1,2,3,4,4a alpha, 12a beta-Hexahydro-7,7,10,- 10-tetramethyl-7H,10H-8,9-dithia-5,12-diazabenzo-cyclodec ene, C14H24N2S2, Mr = 284.49, monoclinic, P2(1)/n, a = 8.962 (1), b = 19.356 (3), c = 10.178 (1) A, beta = 114.49 (1) degrees, V = 1606.7 (7) A3, Z = 4, Dm = 1.21 (1), D chi = 1.176 Mg m-3, mu (Mo K alpha, lambda = 0.71073 A) = 0.31 mm-1, F(000) = 616, T = 296 (1) K, RF = 0.031 for 2066 reflections. The molecule has approximate point symmetry 2 and consists of a 1,2-trans-disubstituted cyclohexane (chair conformation) fused to a ten-membered ring that contains one disulfide and two, trans-substituted, imino groups. Structural parameters associated with the disulfide group, including the C-S-S-C torsion angle [90.8 (1) degrees], are similar to those reported for several acyclic disulfides. The N-C-C-N torsion angle [-63.1 (2) degrees] associated with disubstitution of the cyclohexane ring is substantially larger than those found for protonated or chelated 1,2-trans-diamino-cyclohexane.

Acetyl benzyl disulfide.

S-Benzylthio thioacetate, C9H10OS2, Mr = 198.31, monoclinic, P2(1), a = 5.7112(5), b = 8.1912(5), c = 10.6486(8) A, beta = 92.230(8) degrees, V = 497.8(1) A3, Z = 2, Dm = 1.32(1), Dx = 1.323 Mg m-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.47 mm-1, F(000) = 208, T = 299(1) K, RF = 0.024 for 812 reflections. In this molecule, the S-S [2.024(1) A] and S-C [1.802(3), 1.825(4) A] distances are typical and the C-S-S-C dihedral angle [-80.5(1) degree] lies at the lower end of the range reported for related compounds. The acetyl and disulfide groups are coplanar to within +/- 0.01 A. As a consequence, the molecule exhibits a short [3.078(2) A [intramolecular S...O contact.

Copper chelating agents. A comparison of cupruretic responses to various tetramines and D-penicillamine.

Toxic or hypersensitivity reactions occur frequently with D-penicillamine therapy. Therefore there is a need for effective, well-tolerated alternative chelating agents to control the copper accumulation which occurs in Wilson's disease and some other chronic liver diseases. A group of tetramines (linear and macrocyclic) was surveyed for cupruretic activity and compared to D-penicillamine. 2,3,2-Tetramine was the most effective agent when given either by gavage or intravenously. It was more effective than 2,2,2-tetramine (trien) or D-penicillamine and, in addition, induced a more prolonged cupruresis. Despite their higher formation constants for copper, the macrocyclic tetramines did not induce a significant cupruresis. In this study, the 2,3,2-tetramine was the most effective agent for inducing a cupruresis in both normal and copper-loaded rats. If well tolerated by humans, it could become a useful agent for management of disorders characterized by copper accumulation.