Introducing an α-Keto Ester Functional Group through Pt-Catalyzed Direct C-H Acylation with Ethyl Chlorooxoacetate.

Platinum-catalyzed selective C-H acylation of 2-aryloxypyridines with ethyl chlorooxoacetate provides an efficient way of introducing an α-keto ester functional group. The reaction is oxidant-free, additive-free, and, more significantly, free of any decarbonylative side reactions. The reaction tolerates a variety of substituents from strongly electron-donating to strongly electron-withdrawing groups. Double acylation is feasible for 2-phenoxypyridine and its derivatives with only one substituent at the para position. Although the reaction of 2-(2-methylphenoxy)pyridine with ethyl malonyl chloride did not produce the desired ß-keto ester, the reaction with ethyl succinyl chloride proceeded smoothly to give the γ-keto ester. Ethyl chlorooxoacetate is much more reactive than ethyl succinyl chloride in this Pt-catalyzed C-H acylation reaction.

Theoretical Probe to the Mechanism of Pt-Catalyzed C-H Acylation Reaction: Possible Pathways for the Acylation Reaction of a Platinacycle.

Density functional theory (DFT) and nudged elastic band (NEB) theory have been used to study the possible pathways for the acylation of cycloplatinated complex A derived from 2-phenoxypyridine, which is conceived as the key step in the platinum-catalyzed acylation of 2-aryloxypyridines. Geometry optimization indicates that the previously proposed intermediate, an arenium ion species as a result of analogous aromatic substitution, is not an energy minimum, but rather cationic Pt-arene η2-complex E is obtained as a stable intermediate. NEB simulations suggest that the minimum energy pathway for the acylation reaction has energy barrier of 33.6 kcal/mol and consists of the following steps: (1) Nucleophilic substitution at acetyl chloride by the platinum of the reactant A forms five-coordinate Pt(IV) acylplatinum complex B with an energy barrier of 21.7 kcal/mol. (2) B undergoes 1,2-acyl migration from the platinum to the cyclometalated carbon through a three-membered platinacycle transition state to give Pt-arene η2-complex E with an energy barrier of 14.0 kcal/mol. (3) E undergoes ligand exchange with chloride to form neutral Pt-arene η2-complex F. (4) F undergoes ligand substitution with acetonitrile to give the product and the energy barrier is small (10.6 kcal/mol). The rate-determining step is the 1,2-acyl migration step. It is interesting to note that intermediate F was not included in the proposed mechanism but was identified by the NEB simulations. Five-coordinate Pt(IV) acylplatinum complex B undergoes barrierless ligand coordination with chloride to form neutral formal oxidative addition acylplatinum complex D; however, D is less stable than reactant A by 2.9 kcal/mol, which also implies that the isolation of an oxidative addition product Pt(IV) complex may be very challenging. The direct reductive elimination of D to form product P has a higher energy barrier (36.6 kcal/mol).

Inhibition of Cdc42-intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration, and tumor growth.

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist. In lung cancer cell lines with varying EGFR and Ras mutations as well as both androgen-independent and androgen-dependent prostate cancer cell lines, ZCL367 impeded cell cycle progression, reduced proliferation, and suppressed migration. ZCL367 decreased Cdc42-intersectin interactions and reduced Cdc42-mediated filopodia formation. ZCL367 showed increased potency and selectivity for Cdc42 when compared to Rac1 and RhoA. ZCL367 reduced A549 tumorigenesis in a xenograft mouse model. Altogether, ZCL367 is a selective Cdc42 inhibitor and an excellent candidate for lead compound optimization for further anticancer studies.

Platinum in Chemistry: An Adventure from Phosphorescent Materials to Catalytic C-H Functionalization.

Platinum is a precious and versatile metal and has played important roles in various fields of chemistry ranging from functional materials to anticancer drugs and catalysis. This account highlights an adventurous journey of platinum from promoting phosphorescence to catalyzing a C-H functionalization reaction, or you may consider it our research adventure from phosphorescent materials to catalysis. Interestingly, this journey is driven by a series of "bad" reactions, and of course more importantly by our curiosity about the "bad" reactions. This review will introduce to you a few classes of phosphorescent materials based on tridentate and tetradentate cycloplatinated complexes and related material design strategies, a classical example of thermodynamic and kinetic control of reactions and related platinum-mediated competing sp2 /sp3 C-H activation reactions, an unprecedented regiospecific acylation of cycloplatinated complexes, and a unique platinum-catalyzed oxidant- and additive-free C-H acylation reaction.

Platinum-Catalyzed Double Acylation of 2-(Aryloxy)pyridines via Direct C-H Activation.

A unique, platinum-catalyzed, direct C-H acylation of 2-(aryloxy)pyridines with acyl chlorides is discovered. The reaction requires neither an oxidant nor other additives. When both ortho positions of the aryl group are accessible, the double acylation occurs readily to produce the diacylated products. Aliphatic, aromatic, and α,ß-unsaturated acyl groups can all be introduced. The acylation reaction may proceed through an analogous aromatic electrophilic substitution triggered by the nucleophilic attack of the platinum at the acyl chloride.

Cytotoxicity of cyclometalated platinum complexes based on tridentate NCN and CNN-coordinating ligands: remarkable coordination dependence.

A series of cyclometalated platinum complexes with diverse coordination patterns and geometries were screened for their anticancer activity. It was discovered that the N^C^N-coordinated platinum complex based on 1,3-di(pyridyl)benzene displayed much higher cytotoxicity against human lung cancer cells NCI-H522, HCC827, and NCI-H1299, and human prostate cancer cell RV1 than cisplatin. In a sharp contrast, the C^N^N-coordinated platinum complex based on 6-phenyl-2,2'-bipyridine was ineffective on these cancer cells. This remarkable difference in cytotoxicity displayed by N^C^N- and C^N^N-coordinated platinum complexes was related to the trans effect of the carbon donor in the cyclometalated platinum complexes, which played a crucial role in facilitating the dissociation of the chloride ligand to create an active binding site. The DNA binding was studied for the N^C^N-coordinated platinum complex using electrophoresis and emission titration. The cellular uptake observed by fluorescent microscope showed that the complex is largely concentrated in the cytoplasm. The possible pathways for the cell apoptosis were studied by western blot analysis and the activation of PARP via caspase 7 was observed.

Synthesis, structure, photophysics, and a DFT study of phosphorescent C*N∧N- and C∧N∧N-coordinated platinum complexes.

The reaction of N,N-diphenyl-2,2'-bipyridin-6-amine (L1) and N,N-diphenyl-6-(1H-pyrazol-1-yl)pyridin-2-amine (L2) with K2PtCl4 produced C*N(∧)N-coordinated cycloplatinated compounds with a five-six fused metallacycle 1a and 2a, respectively, which were then converted into their phenylacetylide derivatives 1b and 2b, respectively. Similar reactions starting from 2-phenyl-6-(1H-pyrazol-1-yl)pyridine (L3) produced C(∧)N(∧)N-coordinated platinum complexes 3a and 3b with a five-five-fused metallacycle. The structures of 1a, 1b, 2b, 3a, and 3b were determined by X-ray crystallography. The C*N(∧)N-coordinated platinum complexes are closer to a square geometry, whereas the C(∧)N(∧)N-coordinated complexes display a nearly perfect planar geometry. The π···π interactions were revealed in the crystal packing for 1a, 2b, and 3a with a π···π contact of 3.450, 3.422, and 3.414 Å, respectively. Two conformers were revealed in the crystal structure of 2b, one with the phenyl ring of the phenylacetylide being approximately parallel with the coordination plane and the other with the phenyl ring being approximately perpendicular to the coordination plane. Both 1a and 1b are weakly emissive in the red region. Complexes 2a and 3a are also weakly emissive, but their acetylide derivatives 2b and 3b emitted strongly green light at room temperature with quantum yields of 43 and 62%, respectively. DFT/TDDFT calculations were performed to elucidate the nature of their electronic transitions. The calculations suggested that lowest singlet and triplet excited states are characteristic of a mixed state involving one or more charge-transfer transitions such as ILCT, MLCT, and LLCT.

Highly luminescent tridentate N

A series of cyclometalating ligands, N-phenyl-N-(3-(pyridin-2-yl)phenyl)pyridin-2-amine (L1), N-(3-(1H-pyrazol-1-yl)phenyl)-N-phenylpyridin-2-amine (L2), N-phenyl-N-(3-(quinolin-2-yl)phenyl)pyridin-2-amine (L3), N-phenyl-N-(3-(pyridin-2-yl)phenyl)quinolin-2-amine (L4), N-(3-(isoquinolin-1-yl)phenyl)-N-phenylpyridin-2-amine (L5), and N-phenyl-N-(3-(pyridin-2-yl)phenyl)isoquinolin-1-amine (L6), were synthesized, which reacted with K(2)PtCl(4) in glacial acetic acid to produce N^C*N-coordinated platinum(II) complexes featured in a fused five-six-membered metallacycle, 1-6, respectively. The structures of 1, 3, 4, and 6 were determined by single crystal X-ray crystallography. The square geometries of the complexes are improved when compared with those of the N^C^N-coordinated complexes as the bite angles for the platinum in N^C*N-coordinated complexes 1, 3, and 4 are increased. The Pt-C bonds (1.94-1.95 Å) are shorter than those of C^N^N-coordinated platinum complexes but longer than those found for N^C^N-coordinated platinum complexes. With the increase of the steric interaction, the distortion of the molecules from a planar coordination geometry becomes more and more severe from 1 to 3 to 4 and 6, and in 6, the N-phenyl ring has to stand up on the coordination sphere to minimize the steric interaction with the N-isoquinolyl ring. The photophysical properties of the complexes were studied, and their absorption and emission spectra were interpreted by relating to the structural features revealed by the X-ray crystal structures and the orbital characters predicted by DFT calculations. All complexes are emissive in fluid at room temperature, and the quantum yields (up to 0.65) are comparable to those of highly emissive N^C^N-coordinated platinum complexes. Self-quenching was not observed in the concentration range of 10(-6) to 10(-4) M. Large rigidochromic shifts for the emissions of 2, 4, and 6 upon cooling from room temperature to rigid glass (77 K) were observed. Two different triplet states that control the emissions were proposed to account for the photophysical properties of 6.

Hydroxycamptothecin-loaded Fe3O4 nanoparticles induce human lung cancer cell apoptosis through caspase-8 pathway activation and disrupt tight junctions.

10-Hydroxycamptothecin (HCPT) elicits strong anti-cancer effects and is less toxic than camptothecin (CPT), making it widely used in recent clinical trials. However, its low solubility limits its application as an effective anti-cancer therapy. In the present study we investigate the hypothesis that the unique water dispersible oleic acid-Triton X-100-coated Fe3O4 nanoparticles loaded with HCPT disrupt epithelial cell-cell junctions and induce human lung cancer cell apoptosis through the caspase-8 pathway. We characterized the HCPT-loaded nanoparticles and determined their effects on lung cancer cell viability and apoptosis by using immunofluorescence light microscopy and SDS-PAGE/immunoblots. We found that HCPT-loaded nanoparticles elicited an anti-proliferative effect in a dose-dependent manner. HCPT-loaded nanoparticles reduced the expression of cell-cell junction protein claudins, E-cadherin and ZO-1, and transmission electron microcopy demonstrated a disrupted tight junction ultrastructure. Transepithelial electric resistance was also reduced, indicating the reduction of tight junction functions. The HCPT-loaded nanoparticles increased phosphorylation of p38 and SAPK/JNK while it showed no effects on p42/44 MAP kinase. Compared with void Fe3O4 nanoparticles or HCPT drug alone, HCPT drug-loaded nanoparticles evoked synergistic effects by increasing cell apoptosis with enhanced activation of the caspase-8 pathway. Therefore, our current study highlights the potential of HCPT drug-loaded nanoparticles as a chemotherapeutic agent for increasing anti-cancer drug efficacy.

Solvent-controlled switch of selectivity between sp2 and sp3 C-H bond activation by platinum(II).

By merely changing the solvent, two different cyclometalated platinum complexes resulted from either sp(2) or sp(3) C-H bond activation can be prepared selectively. For example, the reaction of L1 with K(2)PtCl(4) in MeCN gave exclusively kinetic product 1a, while the reaction in AcOH was thermodynamically controlled and produced predominantly 1b.

Photophysical properties of the series fac- and mer-(1-phenylisoquinolinato-N∧C2')(x)(2-phenylpyridinato-N∧C2')(3-x)iridium(III) (x = 1-3).

The photophysical properties of tris-cyclometalated iridium(III) complexes have been probed by chemical and geometric variation through the series fac- and mer-Ir(piq)(x)(ppy)(3-x) (x = 1-3; piq = 1-phenylisoquinolinato-N(∧)C(2'), ppy = 2-phenylpyridinato-N(∧)C(2')). The phosphorescent decays were recorded in solution at 295 K and in polymer films from 2 to 295 K. In the heteroleptic complexes, emission occurs based solely on the piq ligand(s), at least by the nanosecond time scale, as its excited states are the lowest energy. Because fac-Ir(piq)(3) and fac-Ir(ppy)(3) possess practically the same oxidation potential, comparison of photophysical properties through the series fac-Ir(piq)(x)(ppy)(3-x) (x = 1-3) revealed the effects of having one, two, or three emissive piq ligands with no confounding effects from differences in electron withdrawing or donating properties between the spectator ppy ligands and the piq ligands. Effects of placement of piq ligands in different coordination geometries were elucidated by comparisons to the mer series.

Improvement in phosphorescence efficiency through tuning of coordination geometry of tridentate cyclometalated platinum(II) complexes.

A series of tridentate cyclometalated platinum(II) complexes (C(∧)N*N)PtL (L = Cl or acetylide) featuring a fused five-six-membered metallacycle were synthesized. The structure of the complexes was confirmed by X-ray crystallography. In contrast to the C(∧)N(∧)N platinum complexes with a fused five-five-membered metallacycle, the platinum coordination in C(∧)N*N complexes is much closer to a square planar geometry. The photophysical properties of the complexes were studied. The geometrical change from C(∧)N(∧)N to C(∧)N*N led to a substantial improvement in phosphorescence efficiency of the complexes with an acetylide ligand in solution at room temperature. For example, the quantum yield of (C(∧)N*N)PtCCPh was measured to be 56%, demonstrating a big jump from 4% reported for (C(∧)N(∧)N)PtCCPh.

Highly luminescent tetradentate bis-cyclometalated platinum complexes: design, synthesis, structure, photophysics, and electroluminescence application.

N,N-Di(6-phenylpyridin-2-yl)aniline (L1), N,N-di(6-(2,4-difluorophenyl)pyridin-2-yl)aniline (L2), N,N-di(3-(pyridin-2-yl)phenyl)aniline (L3), N,N-di(3-(1H-pyrazol-1-yl)phenyl)aniline (L4), N,N-di(3-(3-methyl-1H-pyrazol-1-yl)phenyl)aniline (L5), and N,N-di(3-(4-methyl-1H-pyrazol-1-yl)phenyl)aniline (L6) undergo cyclometalation to produce two types of tetradentate bis-cyclometalated platinum(II) complexes: C--N*N(wedge)C platinum complexes 1 and 2 and N--C*C--N platinum complexes 3-6, respectively, where an "X--Y" (X, Y = C or N) denotes a bidentate coordination to the platinum to form a five-membered metallacycle and "X*Y" denotes a coordination to form a six-membered metallacycle. The crystal structures of 1, 3, and 5 were determined by the single-crystal X-ray diffraction analysis, showing distorted square-planar geometry, that is, two C--N coordination moieties are twisted. Complex 5 showed much greater distortion with largest deviation of 0.193 A from the mean NCCNPt coordination plane, which is attributed to the steric interaction between the two 3-methyl groups on the pyrazolyl rings. Density functional theory (DFT) calculations were carried out on the ground states of 1 and 3-6. The optimized geometries are consistent with the crystal structures. The highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the molecules displayed a localized characteristic with the contribution (18-45%) of the platinum metal to the HOMOs. All complexes are emissive at ambient temperature in fluid with quantum yields of 0.14 to 0.76 in 2-methyltetrahydrofuran. The emission of the complexes covers from blue to red region with lambda(max) ranging from 474 to 613 nm. Excimer emission was observed for 1 and 2 at high concentration of the complexes. The emission lifetime at infinite dilution for 1 and 2 was determined to be 7.8 and 11.4 micros, respectively. Concentration quenching was observed for 3 and 4, but the excimer emission was not observed. The life times for 3-6 were determined to be in the range of micro seconds, but those of 4-6 (3.4-5.7 micros) were somewhat shorter than that of 3 (7.6 micros). The highly structured emission spectra, long life times, and DFT calculations suggested that the emissive state is primarily a (3)LC state with metal-to-ligand charge-transfer (MLCT) admixture. The ZFS of 23 cm(-1) for the emissive triplet state was observed directly by high resolution spectroscopy for 1 in a Shpol'skii matrix, which also suggested an emission from a triplet ligand centered ((3)LC) state with admixture of MLCT character. Complex 1 was incorporated into an organic light-emitting diode (OLED) device as an emitter at 4 wt % in the mixed host of 4,4',4''-tris(N-carbazolyl)triphenylamine (TCTA) and 2,2',2''-(1,3,5-benzenetriyl)tris(1-phenyl-1-H-benzimidazole) (TPBI) and demonstrated excellent performance with maximum external quantum efficiency of 14.7% at the current density of 0.01 mA/cm(-1).

Acridinone/amine(carbazole)-based bipolar molecules: efficient hosts for fluorescent and phosphorescent emitters.

Three acridinone-based molecules ADBP, ACBP, and DABP were synthesized, and their application to the OLED devices was investigated. When used as the host for either the deep blue singlet or the green triplet emitter in OLED devices, the bipolar molecules ADBP and ACBP demonstrated superior performance compared to either DABP or commonly used host CBP, remarkably lowering the drive voltage and improving efficiencies.

Highly efficient, selective, and general method for the preparation of meridional homo- and heteroleptic tris-cyclometalated iridium complexes.

A highly efficient and general method based on transmetalation with an organozinc reagent is developed for selective preparation of homo- and heteroleptic meridional tris-cyclometalated iridium complexes. The molecular structure of mer-Ir(1-piq)2(ppy) (2) has been determined by a single-crystal X-ray diffraction analysis. The emission properties of a series of meridional complexes are reported.

Highly efficient, general procedure for the preparation of alkylzinc reagents from unactivated alkyl bromides and chlorides.

[reaction: see text] Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal (dust, powder, granule, shot), activated with 1-5 mol % I(2), into alkyl bromides in a polar aprotic solvent. The zinc reagents thus formed undergo Ni- and Pd-catalyzed cross-coupling with aryl halides to produce functionalized alkylarenes in excellent yields.

A novel, highly selective, and general methodology for the synthesis of 1,5-diene-containing oligoisoprenoids of all possible geometrical combinations exemplified by an iterative and convergent synthesis of coenzyme Q(10).

[reaction: see text] A truly general, versatile, and highly regio- and stereoselective methodology for the synthesis of terpenoids containing 1,5-diene units of E and/or Z geometry critically involves Pd-catalyzed homoallyl- and homopropargyl-alkenyl coupling and Zr-catalyzed carboalumination of alkynes. By using this methodology, coenzyme Q(10), (E,Z,E)-geranylgeranoil, and other natural or unnatural compounds have been synthesized efficiently.