Reductive silylation of Cp*UO2((Mes)PDI(Me)) promoted by Lewis bases.

Functionalization of the uranyl moiety (UO2(2+)) in Cp*UO2((Mes)PDI(Me)) (1-PDI) ((Mes)PDI(Me) = 2,6-((Mes)N=CMe)2C5H3N; Mes = 2,4,6-triphenylmethyl), which bears a reduced, monoanionic pyridine(diimine) ligand, is reported. Silylating reagents, R3Si-X (R = Me, X = Cl, I, OTf, SPh; R = Ph, X = Cl), effectively add across the strong O=U=O bonds in the presence of the Lewis base, OPPh3, generating products of the form (R3SiO)2UX2(OPPh3)2 (R = Me, X = I (2-OPPh3), Cl (3-OPPh3), SPh (5-OPPh3), OTf (6-OPPh3); R = Ph, X = Cl (4-OPPh3)). During this transformation, reduction to uranium(iv) occurs with loss of (Cp*)2 and (Mes)PDI(Me), each of which acts as a one-electron source. In the reaction, the Lewis base serves to activate the silyl halide, generating a more electrophilic silyl group, as determined by (29)Si NMR spectroscopy, that undergoes facile transfer to the oxo groups. Complete U-O bond scission was accomplished by treating the uranium(iv) disiloxide compounds with additional silylating reagent, forming the family (Ph3PO)2UX4. All compounds were characterized by (1)H NMR, infrared, and electronic absorption spectroscopies. X-ray crystallographic characterization was used to elucidate the structures of 2-OPPh3, 4-OPPh3, 5-OPPh3, and 6-OPPh3.

Mild synthesis of a family of planar triazinium cations via proton-assisted cyclization of pyridyl containing azo compounds and studies on DNA intercalation.

An efficient synthesis of a family of heteroaromatic triazinium compounds, [2a]X-[2g]X (X = Cl, ClO4, NO3, and HSO4), from 2-(arylazo)pyridines via proton-catalyzed heterocyclization is described. Characterization of the compounds is made by different spectroscopic, electrochemical techniques, as well as single-crystal structure determination of the triflate salt of a representative compound, [2a]CF3SO3. The bond parameters indicate that the tricyclo compound, 2a(+), is planar and aromatic with a N-N bond length of 1.275(6) A. These exhibited fluorescence with an emission maximum in the range of 540-535 nm with moderate quantum yields. The triazinium salts can be reduced in two successive one-electron steps as probed by cyclic voltammetry and coulometry. The paramagnetic radical intermediate 2a(*) is distinguished by a sharp and intense EPR spectrum. Fluorescence spectroscopy, circular dichroism, cyclic voltammetry, viscosity measurements, together with DNA melting studies have been used to characterize the binding of 2a(+) with calf thymus DNA. The emission quenching of the compound by [Fe(CN)6](4-) decreased when bound to DNA. As determined by a MTT assay, 2a(+) exhibited significant cytotoxicity at a higher concentration range of 1 mg/mL to 1 microg/mL; however, the % survival ratio increased with dilution. Cellular uptake studies of the referenced compound were followed by FACS analysis.

The stereochemical outcome of electrophilic addition reactions on the 5,6-double bond in the spinosyns.

The electrophilic addition of reagents to the 5,6-double bond in spinosyn A and spinosyn D systems occurred with high pi-diastereofacial selectivity. Addition occurred preferentially from the beta face of the molecule with selectivities ranging from 5:1 to better than 30:1. Various NMR properties were investigated in order to distinguish the beta and alpha isomers with the help of theoretical models of the products. These NMR properties include a (13)C gamma effect to C-11 and vicinal coupling between H-4 and H-5. To help rationalize the selectivity, computational studies on the transition states for epoxidation were calculated using density functional theory. The results indicate that beta epoxidation is favored and that the geometries of the transition structures are consistent with torsional steering being the source of the selectivity.

Preparation and evaluation of sulfide derivatives of the antibiotic brefeldin a as potential prodrug candidates with enhanced aqueous solubilities.

Several sulfide (+)-brefeldin A (BFA) analogues were prepared through the Michael addition of various thiols. Many of the sulfides were also oxidized to the corresponding sulfoxide with m-CPBA. The sulfides were designed to act as BFA prodrugs via the metabolic oxidation to the sulfoxide and subsequent syn elimination. Kinetic experiments were used to prove that the syn elimination of the sulfoxides prepared did in fact take place. Five selenide BFA prodrugs were also prepared that are envisioned to act in the same manner as the sulfides. As expected, when oxidation of the selenide to selenoxide was attempted, in situ syn elimination was observed. All of the compounds prepared were evaluated for antiproliferative activity against human cancer cell lines in the National Cancer Institute screen. The sulfoxides were much more potent than either the sulfides or selenides. Especially notable were sulfoxide 21, which possessed a cytotoxicity mean graph midpoint value (MGM) value lower than BFA itself, and sulfoxide 22, which possessed an MGM value slightly less potent than that of BFA. The sulfide analogues were shown to possess increased aqueous solubilty with respect to BFA.

Mixed-metal assemblies containing multiply bonded dirhenium species linked through thiocyanate- and cyanide-containing bridging units.

The lability of the terminal Re-Cl bond that is cis to the bridging CO ligand in the edge-sharing bioctahedral complexes Re(2)(mu-Cl)(mu-CO)(mu-PP)(2)Cl(3)(L), where PP = Ph(2)PC(=CH(2))PPh(2) (dppE) when L = CO (1) and PP = Ph(2)PCH(2)PPh(2) (dppm) when L = CO (2) or XyINC (3), has been exploited in the preparation of mixed-metal Re(4)Pd(2), Re(2)Ag, Re(2)W, Re(2)Pt, and Re(2)Rh assemblies, in which the dirhenium units are bound to the other metals through NCS or CN bridges. These complexes, which retain the Re=Re bonds of the parent dirhenium complexes, comprise the novel centrosymmetric complex [Re(2)Cl(3)(mu-dppE)(2)(CO)(2)(mu-NCS)](2)Pd(2)(mu-SCN)(mu-NCS)Cl(2) (9), and the trimetallic complexes Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu-NC)Ag(CN)] (10), Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu-NC)W(CO)(5)] (11), [Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu-NC)Pt(CN)(CN-t-Bu)(2)]]PF(6) (12), [Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu-N(CN)(2))Rh(CO)(PPh(3))(2)]]O(3)SCF(3) (13), and Re(2)Cl(3)(mu-dppm)(2)(CO)(2)[(mu-NC)W(CO)(5)] (16). The identities of 9 and 16 have been established by X-ray crystallography, and all complexes characterized by IR and NMR spectroscopy and cyclic voltammetry. The reactions of the dicarbonyl complex 1, and the isomeric pair of complexes Re(2)Cl(4)(mu-dppm)(2)(CO)(CNXyl), which have edge-sharing bioctahedral (ESBO) (3) and open bioctahedral (OBO) (4) geometries, with Na[N(CN)(2)] and K[C(CN)(3)] have been used to prepare complexes in which the uncoordinated CN groups have the potential to coordinate other mono- or dimetal units to form extended arrays. The complexes which have been prepared and characterized are the monosubstituted species Re(2)Cl(3)(X)(mu-dppE)(2)(CO)(2) (X = N(CN)(2) (14) or C(CN)(3) (15)) and Re(2)Cl(3)(X)(mu-dppm)(2)(CO)(CNXyl) (X = N(CN)(2) (17) or C(CN)(3) (18) with ESBO structures; X = N(CN)(2) (19) or C(CN)(3) (20) with OBO structures), of which 15, 18, and 20 have been characterized by single-crystal X-ray structure determinations. The substitutional labilities of the Re-Cl bonds in the complexes Re(2)Cl(4)(mu-dppm)(2)(CO) (5), Re(2)Cl(4)(mu-dppm)(2)(CNXyl) (6), and Re(2)Cl(4)(mu-dppm)(2) (7) toward Na[N(CN)(2)] and K[C(CN)(3)] have also been explored and the complexes Re(2)Cl(3)(X)(mu-dppm)(2)(CO) (X = N(CN)(2) (21) or C(CN)(3) (22)), Re(2)Cl(3)(X)(mu-dppm)(2)(CNXyl) (X = N(CN)(2) (23) or C(CN)(3) (24)), Re(2)Cl(2)(X)(2)(mu-dppm)(2)(CNXyl) (X = N(CN)(2) (25) or C(CN)(3) (26)), Re(2)[N(CN)(2)](4)(mu-dppm)(2) (27), and Re(2)[C(CN)(3)](4)(mu-dppm)(2) (28) isolated in good yield. Single-crystal X-ray structure determinations of 24, 26, and 27 have shown that the Re-Re triple bonds present in the starting materials 5-7 are retained in these products.

Synthesis and anti-HIV activity of cosalane analogues incorporating two dichlorodisalicylmethane pharmacophore fragments.

A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1(RF), HIV-1(IIIB), and HIV-2(ROD) in cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type. Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4.

Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability.

2-Methoxyestradiol is a cytotoxic human metabolite of estradiol with the ability to bind to the colchicine site of tubulin and inhibit its polymerization, and its 2-ethoxy analogue is even more potent. On the basis of a hypothetical relationship between the structures of colchicine and 2-methoxyestradiol, a B-ring-expanded 2-ethoxyestradiol analogue was synthesized in which the B-ring of the steroid is replaced by the B-ring of colchicine. The synthesis relied on the B-ring expansion of available 6-keto estradiol derivatives as opposed to a total synthesis of the homologated steroid framework. The relative configurations of the acetamido substituents in both epimers of the final product were determined by NOESY NMR and confirmed by X-ray crystallography. The epimer having the 6alpha-acetamido substituent was more active as an inhibitor of tubulin polymerization, and it was also more cytotoxic than the 6beta-epimer. These results are consistent with the proposed structural resemblance of 2-methoxyestradiol and colchicine. Several of the synthetic intermediates proved to be potent inhibitors of tubulin polymerization. On the other hand, a 3,17beta-diacetylated, B-ring-expanded analogue of 2-ethoxyestradiol having a ketone at C-6 resembled paclitaxel (Taxol) in its ability to enhance tubulin polymerization and stabilize microtubules. The corresponding 3-acetate and the 17beta-acetate were both synthesized, and it was determined that the 17beta-acetate, but not the 3-acetate, conferred on the steroid derivative its paclitaxel-like activity.

Structural and photophysical studies of Cu(NN)2+ systems in the solid state. Emission at last from complexes with simple 1,10-phenanthroline ligands.

For a variety of reasons, relating the photophysical properties of a copper phenanthroline to a structure in solution is problematic. To elucidate some of the issues involved, in this paper we describe the crystal and molecular structures of a series of Cu(NN)2(+)-containing systems along with spectral data obtained from the solids themselves. The NN ligands investigated are tmp (3,4,7,8-tetramethyl-1,10-phenanthroline), dpdmp (2,9-diphenyl-4,7-dimethyl-1,10-phenanthroline), dptmp (2,9-diphenyl-3,4,7,8-tetramethyl-1,10-phenanthroline), and dipp (2,9-diisopropyl-1,10-phenanthroline). The results show that a flattening distortion can have a large impact on the spectroscopic properties of a Cu(NN)2+ system, whereas a typical rocking distortion has comparatively little effect. The reflectance spectra of orange or orange-red salts that have approximately perpendicular phenanthroline ligands exhibit absorption bands in the neighborhood of 460 nm along with a shoulder at longer wavelength. In the other limit, when a pronounced flattening distortion occurs and the dihedral angle between ligands is 20 degrees or more off perpendicular, the reflectance spectrum exhibits two distinct visible bands with intense absorption occurring at 525 nm or even longer wavelength. If the phenanthroline ligand lacks bulky substituents in the 2,9 positions, the compound may even be purple, depending on the counterion. Cu(NN)2+ complexes that contain phenyl substituents in the 2,9 positions and exhibit long-wavelength absorption in solution probably adopt a flattened structure in the ground electronic state. In most other systems ground-state flattening is a solid-state effect induced by lattice forces. However, a flattening distortion is an intrinsic attribute of the emissive excited state, although intra- or intermolecular forces can inhibit the effect. In the case of the Cu(dptmp)2+ system, intramolecular steric interactions oppose flattening because the methyl groups in the 3,8 positions control the torsion angles of the neighboring phenyl groups. In the case of [Cu(tmp)2]BPh4, packing interactions induce a small flattening in the crystal, but they also constrain the degree of distortion that can occur in the excited state. As a consequence [Cu(tmp)2]BPh4 exhibits a weak photoluminescence in the solid phase (tau = 15 ns). This is the first report of emission from a bis(phenanthroline)copper(I) system that does not have bulky substituents in the 2 and/or 9 positions of the ligand. The [Cu(tmp)2]BPh4 system crystallizes in space group P2(1)/n with a = 17.4883(4) A, b = 9.86860(10) A, c = 26.3747(6) A, alpha = 90 degrees, beta = 97.7021(8) degrees, gamma = 90 degrees, V = 4510.8(3) A3, and Z = 4. For 12,948 unique data with Fo2 > 2 sigma(Fo2), R = 6.5%. The [Cu(dpdmp)2]PF6 system crystallizes in space group P2/n with a = 16.0722(13) A, b = 8.1100(7) A, c = 16.8937(10) A, alpha = 90 degrees, beta = 93.947(5) degrees, gamma = 90 degrees, V = 2196.8(5) A3, and Z = 2. For 2833 unique data with Fo2 > 2 sigma(Fo2), R = 6.0%. The [Cu(dptmp)2]PF6.THF system crystallizes in space group P1 with a = 12.8486(4) A, b = 13.7341(1) A, c = 15.1678(3) A, alpha = 99.5819(14) degrees, beta = 96.7263(13) degrees, gamma = 97.3311(12) degrees, V = 2591.3(2) A3, and Z = 2. For 13,753 unique data with Fo2 > 2 sigma(Fo2), R = 7.4%. Finally, the [Cu(dipp)2]TFPB system crystallizes in space group P1 with a = 14.2523(3) A, b = 16.0496(4) A, c = 17.5801(3) A, alpha = 112.4150(13) degrees, beta = 105.7480(13) degrees, gamma = 99.6078(11) degrees, V = 3408.7(3) A3, and Z = 2. For 8774 unique data with Fo2 > 2 sigma(Fo2), R = 9.3%.

Reactions of the dirhenium(II) complexes Re2X4(mu-dppm)2 (X = Cl, Br; dppm = Ph2PCH2PPh2) with isocyanides. 21. A comparison with the complexes Re2Cl4(mu-dppE)2 and Re2Cl4(mu-dcpm)2 (dppE = Ph2PC(=CH2)PPh2; dcpm = Cy2PCH2PCy2) and the structural characterization of complexes of the types Re2Cl4(mu-LL)2(CNR), Re2Cl4(mu-LL)2(CNR)2, and [Re2Cl3(mu-LL)2(CNR)3]+ (LL = dppm, dppE, dcpm; R = t-Bu, Xyl).

A study of the reactions between the triply bonded dirhenium(II) complexes Re2Cl4(mu-LL)2, where LL = Ph2PCH2PPh2 (dppm), Ph2PC(=CH2)PPh2 (dppE), or Cy2PCH2PCy2 (dcpm), with the isocyanides t-BuNC and XylNC (Xyl = 2,6-dimethylphenyl) show that complexes of the type Re2Cl4(mu-LL)2(CNR), Re2Cl4(mu-LL)2(CNR)2, and [Re2Cl3(mu-LL)2(CNR)3]+ are formed sequentially. Several of these have been structurally characterized by X-ray crystallography: Re2Cl4(mu-dppm)2(CNXyl) (2), Re2Cl4(mu-dcpm)2(CNXyl) (11), Re2Cl4(mu-dppE)2(CN-t-Bu)2 (6), Re2Cl4(mu-dcpm)2(CN-t-Bu)2 (12), and [Re2Cl3(mu-dppE)2(CN-t-Bu)3]Cl (7). Complex 2 has an A-frame-like structure with a single mu-Cl bridging ligand, whereas for 11 the structure is like that of 2 but without this bridge, viz., Cl2Re(mu-dppm)2ReCl2(CNXyl) with a Re-Cl bond approximately collinear with Re identical to Re. The symmetrical complexes 6 and 12 are essentially isostructural and have an anti-arrangement of the two t-BuNC ligands. Complex 7 has the open bioctahedral structure [(t-BuNC)2ClRe(mu-dppE)2ReCl2(CN-t-Bu)]+, which is quite different from that of the edge-sharing bioctahedron found in salts of the [Re2Cl3(mu-dppm)2(CNXyl)3]+ cation and its neutral congener Re2Cl3(mu-dppm)2(CNXyl)3; preliminary crystallographic data for the latter compound show the structure to be (XylNC)ClRe(mu-Cl)(mu-CNXyl)(mu-dppm)2ReCl(CNXyl) with an all-cis arrangement of XylNC ligands. The Re-Re bond distances of 2, 6, 7, 11, and 12 occur in the range 2.289-2.380 A and are consistent in all instances with the retention of a Re identical to Re bond, albeit weakened by some degree of Re-->CNR(pi*) back-bonding.

Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands.

A series of 10 cationic gallium(III) complexes with hexadentate bis(salicylaldimine) ligands were synthesized, characterized, radiolabeled with 67Ga, and screened in a rat model to assess their potential as 68Ga radiopharmaceuticals for imaging the heart with positron emission tomography. The tris(salicylaldimine) ligand precursors were synthesized by condensation of either bis(3-aminopropyl)ethylenediamine (BAPEN) or bis(2,2-dimethyl-3-aminopropyl)ethylenediamine (DM-BAPEN) with 3 equiv of a salicylaldehyde derivative containing alkyl, alkoxy, or alkylamino substituents in the 4, 5, or 6 position of the aromatic ring. The cationic six-coordinate gallium(III) bis(salicylaldimine) complexes were obtained by reaction of these tris(salicylaldimines) with tris(acetylacetonato)gallium(III). X-ray crystallographic confirmation of the molecular structure of Ga[(4,6-(MeO)2sal)2DM-BAPEN]+I- shows the Ga cation to adopt a pseudo-octahedral N4O2 coordination sphere with a trans configuration. All of the 67Ga complexes are lipophilic with measured octanol/water partition coefficients (P) varying from log P = 0.84 to 3.00. These 67Ga-labeled complexes are all found to exhibit significant myocardial uptake following intravenous administration to rats (ranging from 0.34 to 1.08% of the injected dose in myocardium at 1 min postinjection) combined with the desired myocardial retention of tracer.

Potential gallium-68 tracers for imaging the heart with PET: evaluation of four gallium complexes with functionalized tripodal tris(salicylaldimine) ligands.

Gallium-67 and 68Ga complexes have been synthesized with tripodal hexadentate salicylaldimine ligands derived from 1,1,1-tris(salicylaldiminomethyl)ethane, sal3tame. The four ligands evaluated contained alkoxy substituents (n-BuO-, iso-BuO-, sec-BuO-, and n-PrO-) on the terminal ethane carbon of the ligand backbone. In the case of the n-PrO-derivative, the tris(salicylaldimine) ligand was additionally substituted with methoxy groups in the 5-position of the aromatic rings. The 67Ga and 68Ga-complexes of these ligands were prepared by ligand exchange from 67Ga- or 68Ga-acetylacetonate in ethanol. The nonradioactive Ga[(sal)3tame-O-iso-Bu] complex was similarly prepared and shown by x-ray crystallography to exhibit the expected pseudo-octahedral N3O3(3-) coordination sphere about the Ga3+ center. These Ga-radiotracers are highly lipophilic, as demonstrated by their octanol/water partition coefficients. Log P values of 3.1, 3.1, 2.6, and 2.5 were found for the [(sal)3tame-O-iso-Bu], [(sal)3tame-O-n-Bu], [(sal)3tame-O-sec-Bu], and [(5-MeOsal)3tame-O-n-Pr] complexes, respectively. Following intravenous injection into rats, these complexes are rapidly cleared from the blood and exhibit significant myocardial uptake. At 1 min postinjection, 2.4%, 2.0%, 2.1% and 1.1% of the injected dose was found in the heart for the iso-BuO, n-BuO, sec-BuO, and n-PrO complexes, respectively, dropping to 1.0%, 0.8%, 0.8%, and 0.7% at 5 min. The corresponding heart-to-blood ratios are quite high: 17 +/- 3, 14 +/- 2, 12 +/- 2 and 3.5 +/- 0.4 at 1 min and 14 +/- 4, 10 +/- 1, 10 +/- 1 and 3.2 +/- 0.1 at 5 min postinjection. High quality myocardial images were obtained with PET in a normal dog using data collected from 2 to 10 min following intravenous injection of 68Ga[(sal)3tame-O-iso-Bu].

(-)-Grandisin form Cryptocarya crassinervia.

The known lignan (-)-grandisin [1] has been isolated from Cryptocarya crassinervia by using the brine shrimp lethality test to direct the isolation; its structure and relative stereochemistry have been determined by ir, 1H nmr, ms, and X-ray crystallography as an all-trans alpha, alpha'-diaryl-beta, beta'-dimethyltetrahydrofuran. Compound 1 is not significantly cytotoxic in our panel of human tumor cells.

Two new styryl lactones, 9-deoxygoniopypyrone and 7-epi-goniofufurone, from Goniothalamus giganteus.

Two new styryl lactones, 9-deoxygoniopypyrone [1] and 7-epi-goniofufurone [3], and a known styryl lactone, goniodiol [5], were isolated from the stem bark of Goniothalamus giganteus. The structures were elucidated by ir, ms, 1H-nmr, 13C-nmr, and 1H-1H COSY spectra; the relative configurations were determined by X-ray crystallographic analysis. Unlike goniopypyrone [2] and goniofufurone [4], neither of the new styryl lactones 1 and 3 showed significant bioactivities to human tumor cells. However, goniodiol [5] showed significant and selective cytotoxicity against human lung tumor cells (A-549).

Structural characterization of a metal-based perfusion tracer: copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone).

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone), Cu(PTSM), has been obtained as a dark red crystalline solid from EtOH-DMSO solvent mixture and structurally characterized by x-ray crystallography. The molecule possesses the expected pseudo-square planar N2S2 metal coordination sphere; however, the copper center also interacts through its axial coordination site with the sulfur atom of an adjacent Cu(PTSM) molecule in the crystal lattice. The structure of this compound is compared with the structures of other metal complexes that have been proposed in the nuclear medicine literature as perfusion tracers.