Unprecedented anticancer activities of organorhenium sulfonato and carboxylato complexes against hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells.

Cisplatin and other metal-based drugs often display side effects and tumor resistance after prolonged use. Because rhenium-based anticancer complexes are often less toxic, a novel series of organorhenium complexes were synthesized of the types: XRe(CO)3Z (X = α-diimines and Z = p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, picolinate, nicotinate, aspirinate, naproxenate, flufenamate, ibuprofenate, mefenamate, tolfenamate, N-acetyl-tryptophanate), and their biological properties were examined. Specifically, in hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells, the p-toluenesulfonato, 1-naphthalenesulfonato, 2-naphthalenesulfonato, picolinato, nicotinato, acetylsalicylato, flufenamato, ibuprofenato, mefenamato, and N-acetyl-tryptophanato complexes were found to be far more potent than conventional drug cisplatin. DNA-binding studies were performed in each case via UV-Vis titrations, cyclic voltammetry, gel electrophoresis, and viscosity, which suggest DNA partial intercalation interaction, and the structure-activity relationship studies suggest that the anticancer activities increase with the increasing lipophilicities of the compounds, roughly consistent with their DNA-binding activities.

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity.

The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [(35)S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.

Role of Fe(IV)-oxo intermediates in stoichiometric and catalytic oxidations mediated by iron pyridine-azamacrocycles.

An iron(II) complex with a pyridine-containing 14-membered macrocyclic (PyMAC) ligand L1 (L1 = 2,7,12-trimethyl-3,7,11,17-tetra-azabicyclo[11.3.1]heptadeca-1(17),13,15-triene), 1, was prepared and characterized. Complex 1 contains low-spin iron(II) in a pseudo-octahedral geometry as determined by X-ray crystallography. Magnetic susceptibility measurements (298 K, Evans method) and Mössbauer spectroscopy (90 K, δ = 0.50(2) mm/s, ΔE(Q) = 0.78(2) mm/s) confirmed that the low-spin configuration of Fe(II) is retained in liquid and frozen acetonitrile solutions. Cyclic voltammetry revealed a reversible one-electron oxidation/reduction of the iron center in 1, with E(1/2)(Fe(III)/Fe(II)) = 0.49 V vs Fc(+)/Fc, a value very similar to the half-wave potentials of related macrocyclic complexes. Complex 1 catalyzed the epoxidation of cyclooctene and other olefins with H(2)O(2). Low-temperature stopped-flow kinetic studies demonstrated the formation of an iron(IV)-oxo intermediate in the reaction of 1 with H(2)O(2) and concomitant partial ligand oxidation. A soluble iodine(V) oxidant, isopropyl 2-iodoxybenzoate, was found to be an excellent oxygen atom donor for generating Fe(IV)-oxo intermediates for additional spectroscopic (UV-vis in CH(3)CN: λ(max) = 705 nm, ε ≈ 240 M(-1) cm(-1); Mössbauer: δ = 0.03(2) mm/s, ΔE(Q) = 2.00(2) mm/s) and kinetic studies. The electrophilic character of the (L1)Fe(IV)═O intermediate was established in rapid (k(2) = 26.5 M(-1) s(-1) for oxidation of PPh(3) at 0 °C), associative (ΔH(‡) = 53 kJ/mol, ΔS(‡) = -25 J/K mol) oxidation of substituted triarylphosphines (electron-donating substituents increased the reaction rate, with a negative value of Hammet's parameter ρ = -1.05). Similar double-mixing kinetic experiments demonstrated somewhat slower (k(2) = 0.17 M(-1) s(-1) at 0 °C), clean, second-order oxidation of cyclooctene into epoxide with preformed (L1)Fe(IV)═O that could be generated from (L1)Fe(II) and H(2)O(2) or isopropyl 2-iodoxybenzoate. Independently determined rates of ferryl(IV) formation and its subsequent reaction with cyclooctene confirmed that the Fe(IV)-oxo species, (L1)Fe(IV)═O, is a kinetically competent intermediate for cyclooctene epoxidation with H(2)O(2) at room temperature. Partial ligand oxidation of (L1)Fe(IV)═O occurs over time in oxidative media, reducing the oxidizing ability of the ferryl species; the macrocyclic nature of the ligand is retained, resulting in ferryl(IV) complexes with Schiff base PyMACs. NH-groups of the PyMAC ligand assist the oxygen atom transfer from ferryl(IV) intermediates to olefin substrates.

Salvinorin B meth-oxy-methyl ether.

The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-fur-yl)-9-meth-oxy-meth-oxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octa-hydro-1H-benzo[f]isochromene-7-carboxyl-ate], C(23)H(30)O(8), is a deriv-ative of the κ-opioid salvinorin A with enhanced potency, selectivity, and duration of action. Superimposition of their crystal structures reveals, surprisingly, that the terminal C and O atoms of the MOM group overlap with the corresponding atoms in salvinorin A, which are separated by an additional bond. This counter-intuitive isosterism is possible because the MOM ether adopts the 'classic anomeric' conformation (gauche-gauche), tracing a helix around the planar acetate of salvinorin A. This overlap is not seen in the recently reported structure of the tetra-hydro-pyranyl ether, which is less potent. The classic anomeric conformation is strongly favoured in alk-oxy-methyl ethers, but not in substituted acetals, which may contribute to their reduced potency. This structure may prove useful in evaluating models of the activated κ-opioid receptor.

trans-Bis(hinokitiolato)copper(II) trans-bis(hinokitiolato)palladium(II) cocrystals with (5/1) and (3/2) formulations.

trans-Bis(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)copper(II) trans-bis(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)palladium(II) as the (5/1) and (3/2) composites [Cu(C(10)H(11)O(2))(2)]·0.2[Pd(C(10)H(11)O(2))(2)] and [Cu(C(10)H(11)O(2))(2)]·0.67[Pd(C(10)H(11)O(2))(2)], respectively, where 3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olate is the systematic name for the hinokitiolate anion (hino), are the first mixed-metal cocrystalline products isolated from the M(x)(hino)(y) family of complexes. These cocrystals contain square-planar trans-Cu(hino)(2) and trans-Pd(hino)(2) molecules possessing crystallographic inversion symmetry. The bulk formulation for these cocrystalline compounds is Cu(1-x)Pd(x)(hino)(2), where x is 0.166 (4) for the (5/1) product and 0.399 (4) for the (3/2) product. This bulk formulation is simply a convenient average expression of the whole-molecule substitutional disorder present in these compounds. The M-O bonds are in the range 1.9210 (11)-1.9453 (10) Å, the O-M-O bite angles are in the range 82.94 (4)-83.36 (4)°, and all of the hinokitiolate O atoms are involved in C-H···O hydrogen-bonding interactions.

Absolute configurations of tubulin inhibitors taltobulin (HTI-286) and HTI-042 characterized by X-ray diffraction analysis and NMR studies.

The stereochemistry of the tubulin inhibitors taltobulin HTI-286 (2) and HTI-042 (3) was determined by utilizing the DPFGSE 1D NOE experiment. Single crystal X-ray diffraction analysis further confirmed the absolute configuration of these two compounds, which carry the (S,S,S)-configuration necessary for biological activity.

Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors.

A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.

Bis(hinokitiolato)copper(II): modification (III).

Bis(hinokitiolato)copper(II), Cu(hino)(2), exhibits both antibacterial and antiviral properties, and has been previously shown to exist in two modifications. A third modification has now been confirmed, namely tetrakis(mu(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)tricopper(II)-bis(mu(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis[(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)copper(II)] (1/1), [Cu(C(10)H(11)O(2))(2)](3).[Cu(C(10)H(11)O(2))(2)](2), where 3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olate is the systematic name for the hinokitiolate anion. This new modification is composed of discrete [cis-Cu(hino)(2)](2)[trans-Cu(hino)(2)] trimers and [cis-Cu(hino)(2)](2) dimers. The Cu atoms are bridged by mu(2)-O atoms from the hinokitiolate ligands to give distorted square-pyramidal and distorted octahedral Cu(II) coordination environments. Hence, the Cu(II) environments are CuO(5)/CuO(6)/CuO(5) for the trimer and CuO(5)/CuO(5) for the dimer. Each trimer and dimer has crystallographically imposed inversion symmetry. The trimer has never been observed before, the dimer has been seen only once before, and the combination of the two together in the same lattice is unprecedented. The CuO(5) cores exhibit four strong basal Cu-O bonds [1.915 (2)-1.931 (2) A] and one weak apical Cu-O bond [2.652 (2)-2.658 (2) A]. The CuO(6) core exhibits four strong equatorial Cu-O bonds [1.922 (2)-1.929 (2) A] and two very weak axial Cu-O bonds [2.911 (3) A]. The bite angles for the chelating hinokitiolate ligands range from 83.13 (11) to 83.90 (10) degrees .

A urea adduct of bis(hinokitiolato)copper(II).

Bis(µ(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis[(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)copper(II)]-urea-acetone (1/6/2), [Cu(2)(C(10)H(11)O(2))(4)]·6CH(4)N(2)O·2C(3)H(6)O, where 3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olate is the systematic name for the hinokitiolate anion, contains three novel structural features. First, it contains a bis(hinokitiolato)copper(II) dimer, [Cu(hino)(2)](2), unlike any other, demonstrating that linkage isomerism is another avenue by which Cu(hino)(2) can transmute from one form to another. Second, [Cu(hino)(2)](2) is hydrogen bonded to two urea molecules, indicating that hydrogen bonding cannot yet be discounted from any proposed mechanism of action for the antimicrobial and antiviral properties of bis(hinokitiolato)copper(II). Finally, corrugated urea layers crosslinked by [Cu(hino)(2)](2) dimers are observed, suggesting that a new family of host-guest materials, i.e. metallo-urea clathrates, exists to challenge our understanding of crystal engineering and crystal growth and design. Selected details of the structure are that the [Cu(hino)(2)](2) dimers possess crystallographic inversion symmetry, the Cu atoms have square-pyramidal coordination geometries, the basal Cu-O bonds are in the range 1.916 (2)-1.931 (2) Å, the apical Cu-O bond length is 2.582 (2) Å, the hinokitiolate bite angles are in the range 83.41 (7)-83.96 (8)°, the urea-Cu(hino)(2) interactions have an R(2)(2)(8) motif, and the urea layers result from the close packing of R(8)(6)(28) 'butterflies' and R(8)(6)(24) 'strips of tape'.

Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.

A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.

Modification of the furan ring of salvinorin A: identification of a selective partial agonist at the kappa opioid receptor.

In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Introducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadiazoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR antagonism or any affinity for mu or delta opioid receptors.

(+ac,-ac)-trans-Bis(hinokitiolato)copper(II) and its chloroform disolvate.

The complex trans-bis(hinokitiolato)copper(II) [systematic name: trans-bis(3-isopropyl-7-oxocyclohepta-1,3,5-trienolato)copper(II); abbreviated name: trans-Cu(hino)2], [Cu(C10H11O2)2], is a biologically active compound. Three polymorphs of this square-planar monomer, all with (+sp,-sp) isopropyl substituents, have been reported previously. A fourth polymorph containing (+ac,-ac) isopropyl groups and its chloroform disolvate, [Cu(C10H11O2)2].2CHCl3, both exhibiting nonmerohedral twinning and with all Cu atoms on centers of crystallographic inversion symmetry, are reported here. One of the differences between all of these polymorphs is the relative conformation of the isopropyl groups with respect to the plane of the molecule. Stacking and Cu...olefin pi distances ranging from 3.214 (4) to 3.311 (2) A are observed, and the chloroform solvent molecules participate in bifurcated C-H...O hydrogen bonds [H...O = 2.26-2.40 A, C...O = 3.123 (5)-3.214 (5) A, C-H...O = 127-151 degrees and O...H...O = 74 degrees].

Thermal C1-C5 diradical cyclization of enediynes.

Computational studies at the BLYP/6-31G(d) level (supplemented by BCCD(T)/cc-pVDZ calculations) suggest that in aryl-substituted 1,2-diethynylbenzenes, steric effects disfavor the thermal C1-C6 diradical cyclization reaction (Bergman) and electronic effects favor the regiovariant C1-C5 cyclization to the extent that the C1-C5 process should become an important reaction pathway in the thermolyses of such compounds. Experimentally, thermolyses of 1,2-bis(2,4,6-trichlorophenylethynyl)benzene, a particularly favorable case, yields only products derived from C1-C5 cyclization [specifically, 1-(2,4,6-trichlorobenzylidene)-2-(2,4,6-trichlorophenyl)-1H-indene and its hydrogenation product 3-(2,4,6-trichlorobenzyl)-2-(2,4,6-trichlorophenyl)-1H-indene], and even for the parent hydrocarbon 1,2-bis(phenylethynyl)benzene, the formation of C1-C5 cyclization products is competitive with the major Bergman reaction. Although some C1-C5 cyclization products are probably formed by transfer hydrogenation from 1,4-cyclohexadiene (commonly included in such reactions), thermolyses in the absence of 1,4-CHD as well as deuterium labeling studies confirm the existence of direct C1-C5 diradical cyclizations for diaryl-substituted enediynes.

Autoreduction of Pd-Co and Pt-Co cyanogels: exploration of cyanometalate coordination chemistry at elevated temperatures.

Cyanogels are coordination polymers made from the reaction of a chlorometalate and a cyanometalate in aqueous solution, which undergo a sol-gel transition to form stable gels. At temperatures above 240 degrees C, the cyanide ligand acts as a reducing agent and reduces the metal centers to lower oxidation states. To understand the mechanism of the autoreduction, the thermal reduction of the Pd-Co cyanogel system formed by the reaction of PdCl4(2-) and Co(CN)6(3-) was studied in an inert atmosphere. It was found that the reduction proceeds through two polymeric cyanide-containing intermediates, CoPd(CN)4 and Pd(CN)2, that form upon reduction of Co(3+) to Co(2+) and involves a significant rearrangement of the coordination structure. The two intermediates upon further heating reduce to metallic products, which by solid-state diffusion form a single Pd/Co alloy product. CoPd(CN)4 was found to have a hydrated form Co(H2O)2Pd(CN)4 x 4 H2O with a layered structure crystallizing in an orthorhombic Pnma space group. The Pt-Co cyanogel was found to autoreduce via a similar route. CoPt(CN)4 was confirmed as an intermediate. Understanding of the mechanism of the cyanogel autoreduction is an important step toward better understanding of opportunities that cyanogels offer in materials chemistry, as well as an expansion of the knowledge of coordination chemistry at elevated temperatures in general.

Configurationally stable longitudinally twisted polycyclic aromatic compounds.

Two strategies for the synthesis of configurationally stable twisted polycyclic aromatic compounds (PACs) were pursued. The first approach employed dissymmetrically positioned 1-naphthyl substituents to bias the direction of twist in highly substituted PACs. 2,3-Bis(1-naphthyl)-1,4-diphenyltriphenylene (7) was prepared, and its meso cis-dinaphthyl and enantiomeric trans-dinaphthyl isomers were resolved by preparative supercritical fluid chromatography (SFC) on chiral supports. Similarly, several naphthyl-substituted derivatives of the more highly twisted 9,10,11,12,13,14-hexaphenylbenzo[b]triphenylene (2) were prepared. Of these, 10-(1-naphthyl)-9,11,12,14-tetraphenylbenzo[b]triphenylene (13) was resolved by SFC on a chiral support. The pure enantiomers of trans-7 showed moderately large specific rotations ([alpha]D(25) = -330 and +320 degrees), but the specific rotations for the enantiomers of 13 were unexpectedly small ([alpha]D(25) = -23 and +23 degrees). Computational studies suggest that the latter result is due to presence of a minor conformation of 13 possessing a larger rotation of opposite sign than the major conformation. Both 7 and 13 showed strong circular dichroism and moderately strong circularly polarized luminescence. A byproduct of these syntheses was 9,10,19,21-tetraphenyldiphenanthro[9,10-b:9,10-h]carbazole (15), a very crowded carbazole that exhibits an 81 degree end-to-end twist but is not resolvable. In the second approach, the large, twisted, polycyclic aromatic ligand 9,10,11,12,13,14-hexaphenylbenzo[h]naphtho[2,3-f]quinoline (21, an aza-2) was used to prepare the chiral, cyclometallated iridium(III) complex 4. The ligand 21 was prepared via an unusually stable benzannulated norbornadienone, for which the free energy of activation for decarbonylation was a remarkable 33.5 kcal/mol. The iridium complex 4 proved to be configurationally stable and resolvable by analytical HPLC on chiral supports, but the low solubility of 4 prevented its resolution on a preparative scale. A much more soluble dibutyl analogue of 4 (complex 28) was then prepared, but it was not resolvable on any of the available media.

The solid-state conformation of the topical antifungal agent O-naphthalen-2-yl N-methyl-N-(3-methylphenyl)carbamothioate.

Tolnaftate, a classic antifungal compound, has been found to crystallize from 1:1 (v/v) acetone-water as large flat colorless needles in the centrosymmetric monoclinic space group P21/c. These crystals contain a 50:50 mixture of the (+ap,-sp,+ac,-ac) and (-ap,+sp,-ac,+ac) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) Šfor C-N, C-O and C-S, respectively, and the CNOS and C3N moieties are flat and nearly coplanar with each other, consistent with the C-N bond possessing partial double-bond character. Tolnaftate and the four most closely related N,N-disubstituted thiocarbamates in the Cambridge Structural Database (CSD) all exist as E-conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N-tolyl moiety is positioned trans to the S atom, i.e. the N-aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein-ligand interactions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment.

Estrogen receptor dependent inhibitors of NF-kappaB transcriptional activation-1 synthesis and biological evaluation of substituted 2-cyanopropanoic acid derivatives: pathway selective inhibitors of NF-kappaB, a potential treatment for rheumatoid arthritis.

Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.

Synthesis and biological evaluation of benzodioxanylpiperazine derivatives as potent serotonin 5-HT(1A) antagonists: the discovery of Lecozotan.

A series of benzodioxanylpiperazine derivatives possessing a 4-aryl amide substituent was prepared and evaluated for 5-HT(1A) affinity and functional antagonist activity in vitro and in vivo. All of the compounds in this series possessed high affinity for the human 5-HT(1A) receptor and many displayed potent antagonist activity in vitro and varying degrees of intrinsic activity in vivo. Compound 11c (Lecozotan) was selected for further development and is currently in clinical trials.

Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors.

A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.

Synthesis and structure of a polyphenylene macrocycle related to "cubic graphite".

[structure: see text] Palladium-catalyzed coupling of 1,2-bis(4-bromophenyl)-3,4,5,6-tetraphenylbenzene and the corresponding hexaphenylbenzene bis(boronic acid) gave a mixture of linear and cyclic oligomers of hexaphenylbenzene. An X-ray crystal structure of the tetrameric oligomer showed it to be the polyphenylene macrocycle 4 (C(168)H(112)). The roughly D(2) symmetric macrocycle contains a large central cavity, and it is one of the channel substructures of "phenylogous cubic graphite".