Design, synthesis, and structural and spectroscopic studies of push-pull two-photon absorbing chromophores with acceptor groups of varying strength.

A new series of unsymmetrical diphenylaminofluorene-based chromophores with various strong π-electron acceptors were synthesized and fully characterized. The systematic alteration of the structural design facilitated the investigation of effects such as molecular symmetry and strength of electron-donating and/or -withdrawing termini have on optical nonlinearity. In order to determine the electronic and geometrical properties of the novel compounds, a thorough investigation was carried out by a combination of linear and nonlinear spectroscopic techniques, single-crystal X-ray diffraction, and quantum chemical calculations. Finally, on the basis of two-photon absorption (2PA) cross sections, the general trend for π-electron accepting ability, i.e., ability to accept charge transfer from diphenylamine was: 2-pyran-4-ylidene malononitrile (pyranone) > dicyanovinyl > bis(dicyanomethylidene)indane >1-(thiophen-2-yl)propenone > dicyanoethylenyl >3-(thiophen-2-yl)propenone. An analogue with the 2-pyran-4-ylidene malononitrile acceptor group exhibited a nearly 3-fold enhancement of the 2PA cross section (1650 GM at 840 nm), relative to other members of the series.

Luminescent Fluorene-Based Bis-Pyrazolyl Aniline Ligand for Aluminum Detection.

The design, synthesis, and photophysical properties of a new fluorene-based fluorescent chemosensor, 4-((E)-2-(2-(benzo[d]thiazol-2-yl)-9,9-diethyl-9H-fluoren-7-yl)vinyl)-N,N-bis((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzenamine (AXF-Al), is described for the detection of Al3+. AXF-Al exhibited absorption at 382 nm and strong fluorescence emission at 542 nm (fluorescence quantum yield, Φ F, of 0.80). The capture of Al3+ by the pyrazolyl aniline receptor resulted in nominal change in the linear absorption (372 nm) but a large hypsochromic shift of 161 nm in the fluorescence spectrum (542 to 433 nm, Φ F = 0.88), from which Al3+ was detected both ratiometrically and colorimetrically. The addition of other metal ions, namely Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg 2+ and Pb2+, produced only minimal changes in the optical properties of this probe. The emission band of this probe was also accessed by two-photon excitation in the near-IR, as two-photon absorption (2PA) is important for potential applications in two-photon fluorescence microscopy (2PFM) imaging. The 2PA cross section of the free fluorenyl ligand AXF-Al was 220 GM at 810 nm and 235 GM at 810 nm for the Al-ligand complex, practically useful properties for 2PFM.

Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-pyrano-[2,3-b]naphthoquinones with anticancer activity.

4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses.

Mono- and dicarbonyl-bridged tricyclic heterocyclic acceptors: synthesis and electronic properties.

A series of trialkylsilyl-substituted 2,2'-dithiophene, 4,4'-di-n-hexyl-2,2'-dithiophene, 5,5'-dithiazole, and 2,2'-diselenophene with carbonyl (2a-d) and α-dicarbonyl bridges (3a-d) were prepared from readily available dihalides, using double lithiation followed by trapping with N,N-dimethylcarbamoyl chloride or diethyl oxalate (or N,N-dimethylpiperazine-2,3-dione), respectively. Cyclic voltammetry reveals that the first half-wave reduction potentials for this series of compounds span a wide range, from -1.87 to -0.97 V vs the ferrocene/ferrocenium couple at 0 V (0.1 M (n)Bu(4)NPF(6) in THF). A significant increase of the first half-wave reduction potential (by 0.50-0.67 V) was observed on substitution of the monocarbonyl bridge with α-dicarbonyl. Adiabatic electron affinity (AEA, gas phase) trends determined via density functional theory (DFT) calculations are in good agreement with the electrochemical reduction potentials. UV-vis absorption spectra across the series show a weak absorption band in the visible range, corresponding to the HOMO→LUMO transition within a one-electron picture, followed by a more intense, high-energy transition(s). Single-crystal X-ray structural analyses reveal molecular packing features that balance the interplay of the presence of the bulky substituents, intermolecular π-stacking interactions, and S···O intermolecular contacts, all of which affect the DFT-evaluated intermolecular electronic couplings and effective charge-carrier masses for the crystals of the tricyclic cores.

Synthesis of structurally simplified analogues of pancratistatin: truncation of the cyclitol ring.

Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.

From small structural modifications to adjustment of structurally dependent properties: 1-methyl-3,5-bis[(E)-2-thienylidene]-4-piperidone and 3,5-bis[(E)-5-bromo-2-thienylidene]-1-methyl-4-piperidone.

The molecules of the title compounds, C(16)H(15)NOS(2), (I), and C(16)H(13)Br(2)NOS(2), (II), are E,E-isomers and consist of an extensive conjugated system, which determines their molecular geometries. Compound (I) crystallizes in the monoclinic space group P2(1)/c. It has one thiophene ring disordered over two positions, with a minor component contribution of 0.100 (3). Compound (II) crystallizes in the noncentrosymmetric orthorhombic space group Pca2(1) with two independent molecules in the unit cell. These molecules are related by a noncrystallographic pseudo-inversion center and possess very similar geometries. The crystal packings of (I) and (II) have a topologically common structural motif, viz. stacks along the b axis, in which the molecules are bound by weak C-H...O hydrogen bonds. The noncentrosymmetric packing of (II) is governed by attractive intermolecular Br...Br and Br...N interactions, which are also responsible for the very high density of (II) (1.861 Mg m(-3)).

Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones.

Pyrano[3,2- c]pyridone and pyrano[3,2- c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.

Novel three-component synthesis and antiproliferative properties of diversely functionalized pyrrolines.

Diversely substituted 2-pyrrolines have been prepared by a novel multicomponent process involving a reaction of various N-(aryl- and alkylsulfonamido)-acetophenones with aldehydes and malononitrile. While the reaction is highly regioselective, it is not stereoselective, generating a mixture of cis and trans 2-pyrrolines. A number of analogs from both cis and trans 2-pyrroline libraries were found to have antiproliferative activity in human cancer cell lines.

Homo- and heterometallic luminescent 2-D stilbene metal-organic frameworks.

Metal-organic frameworks (MOFs) can provide a matrix for the assembly of organic chromophores into well-defined geometries, allowing for tuning of the material properties and study of structure-property relationships. Here, we report on the effect of the coordinated metal ion on the luminescence properties of eight isostructural MOFs having the formula M(1)2M(2)L3(DMF)2 (M(1) = M(2) = Zn (1), Cd (2), Mn (3), Co (4); M(1) = Zn, M(2) = Cd (5), Mn (6), Co (7); M(1) = Co, M(2) = Mn (8); L = trans-4,4'-stilbene dicarboxylate), synthesized by reaction of the appropriate metal nitrate or mixtures of metal nitrates with LH2 in DMF. The crystal structures of 2, 3 and 5-8 were determined by X-ray diffraction to be composed of trinuclear metal clusters linked by stilbene dicarboxylate linkers in a paddlewheel geometry, extending to form a 2-D layered structure. In the mixed-metal cases, the larger metal ion was found to occupy the octahedral site in the cluster while the smaller ion occupies the tetrahedral positions, suggesting a selective, ligand-directed assembly process for the mixed-metal species. Variable temperature magnetic measurements for paramagnetic MOFs 3 and 6-8 were consistent with the site occupancies determined crystallographically, and indicated weak intra-cluster antiferromagnetic coupling for 3 and 8. Comparison between the crystal structures of 2, 3 and 5-8 and those reported for 1 and 4 in the literature reveal close resemblances between linker environments, with important intermolecular stilbene-stilbene geometries that are comparable in all cases. Interestingly, pale-colored 1-3 and 5-7 display very similar emission profiles upon excitation at λ(ex) = 350 nm, whereas dark-colored 4 and 8 do not exhibit detectable emission spectra. The bright, well-resolved luminescence of 1, 2 and 5 is ascribed to rigidification of the linker upon coordination to the d(10) metal ions, whereas the weaker emission observed for 3, 6 and 7 is presumably a result of quenching due to close proximity of the linker to one or more paramagnetic ions. Time-resolved measurements for 1, 2, 5 and 6 reveal biexponential emission decays, where the lifetime of the longer-lived state corresponds to observed variations in the nearest-neighbor cofacial stilbene-stilbene distances in their crystal structures. For 3, a monoexponential decay with shorter lifetime was determined, indicating significant paramagnetic quenching of its emissive state.

Reengineered epipodophyllotoxin.

A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.

Two-Photon Absorption Spectrum of a Single Crystal Cyanine-like Dye.

The two-photon absorption (2PA) spectrum of an organic single crystal is reported. The crystal is grown by self-nucleation of a subsaturated hot solution of acetonitrile, and is composed of an asymmetrical donor-π-acceptor cyanine-like dye molecule. To our knowledge, this is the first report of the 2PA spectrum of single crystals made from a cyanine-like dye. The linear and nonlinear properties of the single crystalline material are investigated and compared with the molecular properties of a toluene solution of its monomeric form. The maximum polarization-dependent 2PA coefficient of the single crystal is 52 ± 9 cm/GW, which is more than twice as large as that for the inorganic semiconductor CdTe with a similar absorption edge. The optical properties, linear and nonlinear, are strongly dependent upon incident polarization due to anisotropic molecular packing. X-ray diffraction analysis shows π-stacking dimers formation in the crystal, similar to H-aggregates. Quantum chemical calculations demonstrate that this dimerization leads to the splitting of the energy bands and the appearance of new red-shifted 2PA bands when compared to the solution of monomers. This trend is opposite to the blue shift in the linear absorption spectra upon H-aggregation.

Base-catalyzed halogen dance reaction and oxidative coupling sequence as a convenient method for the preparation of dihalo-bisheteroarenes.

A one-pot preparation of the 2,2'-dibromo-1,1'-bisheteroarenes 3a-d from bromo-heteroarenes utilizing the sequence of the base-catalyzed halogen dance (BCHD) reaction and CuCl(2)-promoted oxidative coupling of the in situ formed alpha-lithio-beta-halo-heteroarenes 2a-d provides a convenient access to precursors for the preparation of tricyclic heteroaromatic cores. The structures of 3a,b,d, 6, and 9 were confirmed by single-crystal X-ray analysis, and dibromides 3a and 3b were used for the preparation of dithieno-[2,3-b:3',2'-d]-pyrrole 10a and its selenophene analogue 10b, respectively.

Synthesis, characterization and structure-activity relationship of novel N-phosphorylated E,E-3,5-bis(thienylidene)piperid-4-ones.

In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-omega-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by (1)H, (31)P, (13)C NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl(3) solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5-bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated.

Structure-cytotoxicity relationship in a series of N-phosphorus substituted E,E-3,5-bis(3-pyridinylmethylene)- and E,E-3,5-bis(4-pyridinylmethylene)piperid-4-ones.

In order to give further insight on the influence of the aromatic ring nature and the presence of the phosphorus substituent at the piperidone nitrogen atom of E,E-3,5-bis((hetero)arylidene)piperid-4-ones on their antitumor properties, a series of phosphorus substituted E,E-3,5-bis(pyridinylmethylene)piperid-4-ones bearing either 3-pyridine or 4-pyridine rings was obtained. Novel NH-3,5-bis(pyridinylmethylene)piperid-4-ones 1a,b were converted into the corresponding N-phosphorylated derivatives 3a-c, 4a-c differing in the substitution at the phosphorus atom (amidophosphates and amidophosphonates), via direct phosphorylation while N-(ω-phosphorylalkyl)-substituted compounds 8a-c were obtained via aldol-crotonic condensation of preformed N-phosphorylalkyl substituted piperidones with the corresponding pyridinecarboxaldehyde. The cytotoxicity screen has revealed that phosphorylated compounds based on E,E-3,5-bis(4-pyridinylmethylene)piperid-4-one framework displayed higher inhibitory properties toward Caov3, A549, KB 3-1 and KB 8-5 human carcinoma cell lines comparing with their analogues with 3-pyridine rings. Introduction of the phosphorus moiety substantially increased the antitumor properties in the case of E,E-3,5-bis(3-pyridinylmethylene)piperid-4-ones derivatives but this influence less pronounced for more active analogues bearing 4-pyridinyl rings. Most of the compounds tested are potent against multi-drug resistant cell line KB 8-5 affording some guidelines for the search of perspective drug-candidates among phosphorus substituted E,E-3,5-bis((hetero)arylidene)piperid-4-ones.

Three-component synthesis and anticancer evaluation of polycyclic indenopyridines lead to the discovery of a novel indenoheterocycle with potent apoptosis inducing properties.

A multicomponent reaction of indane-1,3-dione, an aldehyde and an amine-containing aromatic compound leading to the formation of indenopyridine-based heterocyclic medicinal scaffolds has been investigated. It was found that the yields significantly improve when oxygen gas is bubbled through the reaction mixture, facilitating the oxidation of the intermediate dihydropyridine-containing compounds to their aromatic counterparts. Investigation of the reaction scope revealed that formaldehyde, as well as various aliphatic, aromatic and heteroaromatic aldehydes, works well as the aldehyde component. In addition, substituted anilines and diverse aminoheterocycles can be utilized in this process as the amine-containing component. Preliminary biological evaluation of the synthesized library identified a pyrimidine-based polycycle, which rivals the anticancer drug etoposide in its toxicity and apoptosis inducing properties toward a human T-cell leukemia cell line.