Synthesis, crystal structure, and molecular conformation of N-Ac-dehydro-Phe-L-Val-L-Val-OCH3.

The peptide N-Ac-dehydro-Phe-L-Val-L-Val-OCH3 (C22H31N3O5) was synthesized by the usual workup procedure and finally by coupling the N-Ac-dehydro-Phe-L-Val-OH to valine methyl ester. It was crystallized from its solution in acetonitrile-water mixture at 4 degrees C. The crystals belong to the space group P1 with a = 8.900(3) A, b = 11.135(2) A, c = 12.918(2) A, alpha = 90.36(1) degrees, beta = 110.14(3) 14(3) degrees, V = 1207.7(6) A, 3Z = 2, dm = 1.156(5) Mgm-3, dc = 1.148(5) Mgm-3. The structure was determined by direct methods using SHELXS86. The structure was refined by full-matrix least-squares procedure to an R value of 0.077 for 3916 observed reflections. The molecular dimensions and conformations of the two crystallographically independent molecules are in good agreement. In the dehydro residues, the average C alpha-C beta distance is 1.31(2) A whereas the bond angle C alpha-C beta-C gamma is 132(1) degrees. The average backbone torsion angles are omega 0 = 169(1) degrees, phi 1 = -40(1) degree, psi 1 = -50(1) degree, omega 1 = -177(1) degree, phi 2 = 54(1) degree, psi 2 = 46(1) degree, omega 2 = -174(1) degree, phi 3 = 103(1) degree, psi T3 = -139(1) degree, and theta T3 = -176(1) degree. The acetyl group is in the trans conformation, while the backbone adopts a right-handed and left-handed helical conformation alternatingly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis, crystal structure, and molecular conformation of N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3

The peptide N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3 was synthesized by the usual workup procedure and finally by coupling the N-Boc-L-Phe-dehydro-Leu-OH to valine methyl ester. It was crystallized from its solution in methanol-water mixture at 4 degrees C. The crystals belong to the triclinic space group P1 with a = 5.972(5) A, b = 9.455(6) A, c = 13.101(6) A, alpha = 103.00(4) degrees, beta = 97.14(5) degrees, gamma = 102.86(5) degrees, V = 690.8(8) A, Z = 1, dm = 1.179(5) Mg m-3 and dc = 1.177(5) Mg m-3. The structure was determined by direct methods using SHELXS86. It was refined by block-diagonal least-squares procedure to an R value of 0.060 for 1674 observed reflections. The C alpha 2-C beta 2 distance of 1.323(9) A in dehydro-Leu is an appropriate double bond length. The bond angle C alpha-C beta-C gamma in the dehydro-Leu residue is 129.4(8) degrees. The peptide backbone torsion angles are theta 1 = -168.6(6) degrees, omega 0 = 170.0(6) degrees, phi 1 = -44.5(9) degrees, psi 1 = 134.5(6) degrees, omega 1 = 177.3(6) degrees, phi 2 = 54.5(9) degrees, psi 2 = 31.1(10) degrees, omega 2 = 171.7(6) degrees, phi 3 = 51.9(8) degrees, psi T3 = 139.0(6) degrees, theta T = -175.7(6) degrees. These values show that the backbone adopts a beta-turn II conformation. As a result of beta-turn, an intramolecular hydrogen bond is formed between the oxygen of the ith residue and NH of the (i + 3)th residue at a distance of 3.134(6) A.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis, crystal structure and molecular conformation of N-Ac-dehydro-Phe-L-Val-OH.

The peptide N-Ac-dehydro-Phe-L-Val-OH (C16H20N2O4) was synthesized by the usual workup procedure. The peptide crystallizes from its solution in acetonitrile at 4 degrees in hexagonal space group P6(5) with a = b = 11.874(2)A, c = 21.856(9) A, V = 2668(1) A3, Z = 6, dm = 1.151(3) g cm-3, dc = 1.136(4) g cm-3, CuK alpha = 1.5418 A, mu = 0.641 mm-1, F(000) = 972, T = 293 K. The structure was solved by direct methods and refined by least-squares procedure to an R value of 0.074 for 1922 observed reflections. In the dehydro-residue, the C1 alpha-C1 beta distance is 1.35(1) A while the bond angle C1 alpha-C1 beta-C1 gamma is 131.2(9) degrees. The backbone torsion angles are: omega 0 = 172(1) degrees, phi 1 = -60(2) degrees, psi 1 = -31(2) degrees, omega 1 = -179(1) degrees, phi 2 = 59(2) degrees. These values suggest that the peptide tends to adopt an alternating right-handed and left-handed helical conformation. The side chain torsion angles are: chi 1(1) = -6(2) degrees, chi 1(2.1) = -1(2) degrees, chi 1(2.2) = -178(2) degrees, chi 2(1.1) = 63(2) degrees and chi 2(1.2) = -173(1) degrees. These values show that the side chain of dehydro-Phe is planar whereas the valyl side chain adopts a sterically most preferred conformation. The molecules, linked by intermolecular hydrogen bonds and van der Waals forces, are arranged in helices along the c-axis. The helices are held side-by-side by van der Waals contacts.     

Cell adhesion inhibitory activity of (d)-corynoline, a hexahydrobenzo[c]phenanthridine-type alkaloid, and its structure-activity relationship, studied by X-ray crystal structure analysis and molecular docking study

Corynoline (1), a hexahydrobenzo[c]phenanthridine-type alkaloid, exhibited the concentration-dependent inhibition for the adhesion of human polymorphonuclear leukocyte and eosinophil to human umbilical vein cultured endothelial cell in the concentration range of showing no significant cytotoxicity for the cell: IC(50) value=72.4 microM for (d)-1 and 156.7 microM for (l)-1. This shows the potent anti-inflammatory and/or immunosuppressive activity of 1. To elucidate possible structure-activity relationship, the conformational/structural feature of (d)-1 was investigated by X-ray crystal structure analysis and molecular orbital energy calculations, and the docking study was performed for its interaction with the D1-domain of ICAM-1 (intracellular adhesion molecule-1). A plausible model was proposed, in which all polar atoms of (d)-1 are linked by hydrogen bonds or electrostatic interactions with the functional residues of ICAM-1, that have been supposed to be necessary for the binding with LFA-1 (leukocyte function-associated antigen-1). This suggests the potent inhibitory activity of 1 for the ICAM-1/LFA-1 adhesion and would be important on developing the clinically usable drugs for the inflammatory diseases.     

Synthesis, crystal structure and molecular conformation of Nalpha-Boc-L-leucyl-(Z)-beta-(3-pyridyl)-alpha,beta- dehydroalanyl-L-leucine methyl ester.

A protected tridehydropeptide containing (Z)-beta-(3-pyridyl)-alpha,beta-dehydroalanine (Delta(Z)3Pal) residue, Boc-Leu-Delta(Z)3Pal-Leu-OMe (1), was synthesized via Erlenmeyer azlactone method. X-ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a Delta(Z)Phe analog, Boc-Leu-Delta(Z)Phe-Leu-OMe (2).     

Synthetic amatoxin analogues. II. A proton n.m.r. study of S-deoxo-Ile3-(L)Ala5 and S-deoxo-Ile3-(D)Ala5-amaninamide

Amatoxin analogues with D and L-Ala substitutions in position 5 have been studied by means of 1- and 2-dimensional n.m.r. spectroscopy at 500 MHz. The assignment of all resonances for both analogues has been carried out mostly with the use of COSY and NOESY type experiments. Temperature coefficients for the amide NH protons have been measured and the data compared to known amatoxin structures. The results obtained demonstrate that the rigidity of the bicyclic amatoxin framework is preserved in the D and L-Ala5 analogues, although the temperature coefficients point to intramolecular hydrogen bonds stronger in the case of the L-Ala analogue. The 10-fold decrease of biological activity is discussed in terms of structural features involving also the Trp4 indole accessibility.     

The crystal and molecular structure of cyclo-[-(D-Val-Hyi-Val-D-Hyi)3-] (meso-valinomycin,C60H102N6O18)

The crystal structure of the valinomycin analog, cyclo-[(-D -Val-Hyi-Val-D -Hyi-)₃-] (meso-valinomycin, C₆₀H₁₀₂N₆O₁₈) has been determined by direct x-ray diffraction procedures. The crystals are triclinic, space group P1 , number of molecules per unit cell Z = 1, and cell parameters a = 11.831, b = 13.815, c = 14.889 Å, α = 109.54°, β = 116.10°, γ = 98.89°. The atomic coordinates for the C,N,O atoms were refined in the anisotropic thermal motion approximation and for the H atoms in the isotropic approximation to R = 0.07. The structure is centrosymmetric and has a threefold axis of pseudosymmetry. The depsipeptide chain is in the form of a bracelet stabilized by six identical intramolecular 4 → 1 hydrogen bonds between the amide C?O and NH groups. The ester carbonyls are oriented towards the symmetry axis, their O atoms forming an ellipsoidal molecular cavity. The isopropyl side chains are located on the molecular periphery. The structure found differs considerably from the conformation of the crystalline naturally occurring antibiotic, valinomycin, but completely resembles that of valinomycin and meso-valinomycin in nonpolar solvents. In the crystal, meso-valinomycin molecules form stacks. The molecular cavities situated in the stacks one above the other along the pseudo-C₃ axis form a continuous channel, the internal surface of which is lined by O atoms. The possible conformations of depsipeptides of the valinomycin series and their mode of action in membranes are discussed in the light of the data obtained.     

Synthesis, X-ray crystal structure, anti-fungal and anti-cancer activity of [Ag2(NH3)2(salH)2] (salH2=salicylic acid)

[Ag(2)(NH(3))(2)(salH)(2)] (salH(2)=salicylic acid) was synthesised from salicylic acid and Ag(2)O in concentrated aqueous NH(3) and the dimeric Ag(I) complex was characterised using X-ray crystallography. The complex is centrosymmetric with each metal coordinated to a salicylate carboxylate oxygen and to an ammonia nitrogen atom in an almost linear fashion. The two [Ag(NH(3))(salH)] units in the complex are linked by an Ag-Ag bond. Whilst metal-free salH(2) did not prevent the growth of the fungal pathogen Candida albicans [Ag(2)(NH(3))(2)(salH)(2)], [Ag(2)(salH)(2)] and some simple Ag(I) salts greatly inhibited cell reproduction. SalH(2), [Ag(2)(NH(3))(2)(salH)(2)] [Ag(2)(salH)(2)] and AgClO(4) produced a dose-dependent cytotoxic response against the three human derived cancer cell lines, Cal-27, Hep-G2 and A-498, with the Ag(I)-containing reagents being the most effective.     

Shapes of carcinogenic benz[a]anthracenes: the crystal and molecular structure of 1-methylbenz[a]anthracene.

The crystal structure of 1-methylbenz[a]lanthracene, which is weakly carcinogenic, has been determined by application of direct methods to single-crystal X-ray diffractometric data and refined by least squares to R = 0.09 over 845 independent reflections. Crystals are monoclinic, space group P2(1), with a = 8.491(2), b = 7.138(2), c = 10.500(2)ABEta = 95.06(01), Z = 2. As in other benz[a]anthracenes, the K-region bond C(5)-C(6) is short [1.34(1)A]. The distinctive bay geometry, with a methyl group opposite to a hydrogen, H(12), peri to another hydrogen, H(11), has a long bond C(13)--C(18) = 1.47(1)A in the bay, and the angular benz-ring is inclined at 16.5 degrees to the mean plane of the anthracene fragment. The methyl carbon atom is 0.79 A out of the mean molecular plane (or 0.19 A out of the plane of the benz-ring) and the 1.50 A long C(1)-methyl bond makes angles of 117 degrees and 125 degrees at C(1).     

Synthesis, crystal structure, and molecular conformation of peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH

The peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH was synthesized by the usual workup procedure and finally coupling the N-Boc-L-Pro-dehydro-Phe to glycine. The peptide crystallizes in monoclinic space group P2(1) with a = 8.951(4) A, b = 5.677(6) A, c = 21.192(11) A, beta = 96.97(4) degrees, V = 1069(1) A3, Z = 2, dm = 1.295(5) Mgm-3, and dc = 1.297(4) Mgm-3. The structure was determined by direct methods using SHELXS86. The structure was refined by the block-diagonal least-squares procedure to an R value of 0.074 for 1002 observed reflections. The C alpha 2-C beta 2 distance of 1.33(2) A is an appropriate double bond length. The angle C alpha 2-C beta 2-C gamma 2 is 133(1) degrees. The peptide backbone torsion angles are theta 1 = -167(1) degrees, omega 0 = 179(1) degrees, phi 1 = -48(1) degrees, psi 1 = 137(1) degrees, omega 1 = 175(1) degrees, phi 2 = 65(2) degrees, psi 2 = 15(2) degrees, omega 2 = -179(1) degrees, and phi 3 = -166(1) degrees. These values show that the Boc group has a trans-trans conformation while the peptide backbone adopts a beta-turn II conformation, which is stabilized by an intramolecular hydrogen bond of length of 3.05(1) A. The structures of dehydro-Phe containing peptides suggest that the dehydro-Phe promotes the beta-turn II conformation. The five-membered pyrrolidine ring of the Pro residue adopts an ideal C gamma-exo conformation with torsion angles chi 1(1) = -24(1) degrees, chi 2(1) = 34(1) degrees, chi 3(1) = -30(1) degrees, chi 4(1) = 15(1) degrees, and theta 0(1) = 6(1) degrees. The side-chain torsion angles in dehydro-Phe are chi 1(2) = -1(2) degrees, chi 2,1(2) = -176(1) degrees, and chi 2,2(2) = 8(2) degrees. The plane of C alpha 2-C beta 2-C gamma 2 is rotated with respect to the plane of the phenyl ring at 7(1) degrees, which indicates that the atoms of the side chain of dehydro-Phe are essentially coplanar. The molecules form a 2(1) screw axis related hydrogen-bonded rows along the b axis.     

Hydrogen bonding in the crystal structure of bis[3-([thiomethyl]methyl)pyrazole]copper(II) perchlorate

The ability of a metal-coordinated pyrazole to engage in hydrogen bonding has been explored by synthesis of the title complex, bis[3-([thiomethyl]methyl)pyrazole]copper(II) perchlorate (3). The coordination in 3 can be described as pseudo-octahedral, with two relatively tightly-bound 3-[(thiomethyl)methyl]pyrazole ligands occupying the equatorial plane, forming a [CuN(2)S(2)](2+) unit with the S donors mutually trans to each other. The axial positions are each filled by a weakly bound perchlorate counterion, one oxygen of which forms a hydrogen bond with the pyrazole N-H moiety on an adjacent [CuN(2)S(2)](2+) unit.     

Shapes of benz[a]anthracenes: the crystal and molecular structure of 2-methylbenz[a]anthracene

The crystal structure of 2-methylbenz[a]anthracene (2-MBA), the least carcinogenically active of the monomethylbenz[a]anthracenes, has been determined by application of direct methods to single-crystal X-ray diffractometric data and refined by least squares to R = 0.033 (Rw = 0.035). Deviations of the carbon atoms from the mean molecular plane are much smaller than in the rather more active 1-MBA; in 2-MBA, the benzo-ring A is inclined at about 2 degrees to each of the three rings in the anthracene moiety and even the methyl carbon atom is displaced by only 0.07 A from the ring-carbon atom plane of 2-MBA (and by 0.01 A from the ring-A plane). As in other MBA, the shortest C-C bond in this accurately determined structure is at the K-region (C(5)-C(6) = 1.330(3) A) but three other bonds are short; C(8)-C(9) = 1.347(4), C(10)-C(11) = 1.353(3) and the M-region bond C(3)-C(4) = 1.359(4) A (0.003 A longer if corrected for rigid-body librations). The 2-methyl group appears to take up two orientations with one trio of hydrogen positions more favored than the other.     

Ethylene oligomerization using nickel dithiolene complexes Ni(S2C2R2)2 (R=Ph, CF3) and the crystal structure of Ni[S2C2(CF3)2]2

Nickel bis(dithiolene) complexes have been known for over four decades, yet little is known regarding the chemistry of this important subclass of inorganic coordination complexes in olefin oligomerization or polymerization. We report here that Ni(S(2)C(2)R(2))(2) (R=Ph, CF(3)) are converted to active catalysts for ethylene oligomerization when activated with methylaluminoxane (MAO). The catalyst activity is comparable to some nickel coordination complexes with N-donor ligands under similar conditions. The products are mainly butenes and hexenes, with small amounts of higher oligomers. The product distribution pattern is consistent with a nickel hydride species being the active center, where fast beta-hydride elimination limits the products to mostly butenes and hexenes. The exact nature of the active center and the reaction mechanism remain to be investigated. In addition, we determined the crystal structure for Ni[S(2)C(2)(CF(3))(2)](2). The molecule crystallizes in the P2(1)/n space group and adopts a planar geometry with expected bond lengths and angles. Comparing this structure with that for the donor-acceptor complex with perylene reveals elongation of both the Ni-S and the S-C bonds in the latter, suggesting reduction of Ni[S(2)C(2)(CF(3))(2)](2) may have occurred in the latter.     

Shapes of benz[a]anthracenes: the crystal and molecular structure of 6-methylbenz[a]anthracene

The crystal structure of 6-methylbenz[a]anthracene (6-MBA), a more potent carcinogen than the other K-region monomethyl-substituted benz[a]anthracene (5-MBA), has been determined by application of direct methods to single-crystal X-ray diffractometric data and refined by least squares to R = 0.047 (Rw = 0.053). Deviations of the carbon atoms from planarity are very small with even the methyl carbon displaced by only 0.05 A from the mean molecular plane. The benzo-ring A is inclined at only about 1 1/2 degrees to each of the three rings in the anthracene moiety, i.e. 6-MBA is one of the most nearly planar benz[a]anthracenes. The K-region bond C(5)-C(6) = 1.328(6) A and two other short bonds are C(8)-C(9) = 1.341(7) and C(10)-C(11) = 1.361(7) A in the anthracene D ring.     

Synthesis, crystal structure, cytotoxic activity and DNA-binding properties of the copper (II) and zinc (II) complexes with 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene

A new ligand L, 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene, and its two metal complexes, [Cu(L)3](ClO4)2 (1) and [Zn(L)3](ClO4)2(H2O)2 (2), have been synthesized and characterized. The crystal structure of complex 1 was determined by single crystal X-ray diffraction, which crystallized in monoclinic, space group P2(1)/n with unit cell parameters, a = 12.710(4) angstroms, b = 12.135(3) angstroms, c = 33.450(9) angstroms, beta = 93.281(5) degrees and Z = 4. The Cu atom was six-coordinated to N(1), N(2), N(4), N(5), N(7) and N(8) from three L ligands and formed a slightly distorted octahedral geometry. Complexes 1 and 2, and ligand L were subjected to biological tests in vitro using three different cancer cell lines (HL-60, BGC-823 and MDA-MB-435). Complex 1 showed significant cytotoxic activity against three cancer cell lines. The interactions of complexes 1 and 2, and ligand L with calf thymus DNA were then investigated by thermal denaturation, viscosity measurements and spectrophotometric methods. The experimental results indicated that complexes 1 and 2 bound to DNA by intercalative mode via the ligand L. The intrinsic binding constants of complexes 1 and 2, and ligand L with DNA were 1.8 x 10(4), 5.4 x 10(3) and 2.76 x 10(3) M(-1), respectively.     

Linkage isomerism in the metal complex hexa(thiocyanato)rhenate(IV): Synthesis and crystal structure of (NBu4)2[Re(NCS)6] and [Zn(NO3)(Me2phen)2]2[Re(NCS)5(SCN)]

The linkage isomers [Re(NCS)₆]^2? and [Re(NCS)₅(SCN)]^2? are obtained by the reaction of [ReBr₆]^2? with NCS^? in dimethylformamide. Some differences in the chemical behavior allowed their separation and structural characterization in the form of (NBu₄)₂[Re(NCS)₆] (1) and [Zn(NO₃)(Me₂phen)₂]₂[Re(NCS)₅(SCN)] (2), respectively (Bu = n-C₄H₉ and Me₂phen = 2,9-dimethyl-1,10-phenanthroline).     

Synthesis and PKCtheta inhibitory activity of a series of 4-(indol-5-ylamino)thieno[2,3-b]pyridine-5-carbonitriles

The thieno[2,3-b]pyridine-5-carbonitrile with a 5-indolylamine at C-4 and a phenyl group at C-2 had a moderate activity against PKCθ. Optimization of the groups at C-4 and C-2 led to analog 29, which has an IC₅₀ value of 7.5 nM for the inhibition of PKCθ.     

Model platinum nucleobase and nucleoside complexes and antitumor activity: X-ray crystal structure of [PtIV(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-ethylguanine)Cl]NO3.H2O

A series of platinum(II) and (IV) monoadducts of the type [Pt(II)(DACH)LCl]NO3 and [Pt(IV)(DACH)trans-(X)2LCl]NO3 (where DACH=trans-1R,2R-diaminocyclohexane, L=adenine, guanine, hypoxanthine, cytosine, adenosine, guanosine, inosine, cytidine, 9-ethylguanine (9-EtGua), or 1-methylcytosine and X=hydroxo or acetato ligand) have been synthesized and characterized by elemental analysis and by 1H and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the model nucleobase complex [Pt(IV)(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-EtGua)Cl]NO3.H2O was determined using a single crystal X-ray diffraction method. The compound crystallized in the monoclinic space group P2(1), with a=10.446(2) A, b=22.906(5) A, c=10.978(2) A, Z=4, and R=0.0718, based upon the total of 11,724 collected reflections. In this complex, platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogen of DACH, whereas, the other two equatorial positions occupied by chloride ion and 9-ethylguanine. The remaining two axial positions were occupied by the oxygen atoms of acetato ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. Some of these synthesized models of DACH-Pt-DNA adducts have good in vitro cytotoxic activity against the cisplatin-sensitive human cancer ovarian A2780 cell line (IC50=1-8 microM). Interestingly, a substituted nucleobase (9-ethylguanine) adduct was over 6-fold more potent than regular adducts. The cross-resistance factor against the 44-fold cisplatin-resistant 2780CP/clone 16 cells was about 3-9; thus, the cytotoxicity of adducts was indicative of low potency, but the resistance factors were also substantially low. These results suggest that DNA adducts of DACH-Pt are cytotoxic with low cross-resistance.