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The mono and bis N-heterocyclic carbene (NHC) complexes Ru(ICy)(PPh3)2(CO)H2 (1) and Ru(ICy)2(PPh3)(CO)H2 (2) (ICy = 1,2-dicyclohexylimidazol-2-ylidene) were isolated from the reaction of Ru(PPh3)3(CO)H2 with ICy at elevated temperature. X-ray crystallography revealed that 1 contains a trans arrangement of the PPh3 ligands with the ICy trans to hydride; in complex 2, the two ICy ligands are cis to one another. Both 1 and 2 undergo H/D exchange with D2, as well as reacting rapidly with CO to give Ru(ICy)(PPh3)(CO)3 (3) and Ru(ICy)2(CO)3 (4). Addition of CO2 to solutions of 2 resulted in insertion into one of the Ru−H bonds to afford both the κ¹- and κ²-formate complexes Ru(ICy)2(PPh3)(CO)(κ¹-OCHO)H (5) and Ru(ICy)2(CO)(κ²-OCHO)H (6). Addition of CO2 to 1 gave solely Ru(ICy)(PPh3)(CO)(κ²-OCHO)H (7). The product from reaction of ICy with Ru(PPh3)3HCl proves to be solvent dependent, generating two isomers of the mono-NHC complex Ru(ICy)(PPh3)2HCl (8a,b) in dichloromethane but the bis-NHC species Ru(ICy)2(PPh3)HCl (10) in THF. An agostic interaction between Ru and a β-CH2 hydrogen of the ICy ligand is apparent both in the X-ray crystal structure of 8a and also in solution. This interaction is broken upon addition of CO, which yields Ru(ICy)(PPh3)2(CO)HCl (9). The molecular structure of the coordinatively unsaturated species 10 is devoid of any agostic bonding.

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17β-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]-pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1‘-methoxyethyl derivative, 41, with an IC50 of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1‘-isobutyl derivative, 37, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5‘-linked amides from which 73 emerged. This pyridylethyl amide had an IC50 of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17β-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.

Efficient and flexible syntheses of 2-substituted estrone, estradiol and their 3-O-sulfamate (EMATE) derivatives have been developed using directed ortho-lithiation methodology. 2-Substituted EMATEs display a similar antiproliferative activity profile to the corresponding estradiols against a range of human cancer cell lines. 2-Methoxy (3, 4), 2-methylsulfanyl (20, 21) and 2-ethyl EMATEs (32, 33) proved the most active compounds with 2-ethylestradiol-3-O-sulfamate (33), displaying a mean activity over the NCI 55 cell line panel 80-fold greater than the established anticancer agent 2-methoxyestradiol (2). 2-Ethylestradiol-3-O-sulfamate (33) was also an effective inhibitor of angiogenesis using three in vitro markers, and various 2-substituted EMATEs also proved to be inhibitors of steroid sulfatase (STS), a therapeutic target for the treatment of hormone-dependent breast cancer. The potential of this novel class of multimechanism anticancer agents was confirmed in vivo with good activity observed in the NCI hollow fiber assay and in a MDA-MB-435 xenograft mouse model.

Structure-based drug design using the crystal structure of human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) led to the discovery of novel, selective, and the most potent inhibitors of 17β-HSD1 reported to date. Compounds 1 and 2 contain a side chain with an m-pyridylmethyl-amide functionality extended from the 16β position of a steroid scaffold. A mode of binding is proposed for these inhibitors, and 2 is a steroid-based 17β-HSD1 inhibitor with the potential for further development.

New, yet unprecedented molecular structures with parallel fluorene units were found by X-ray diffraction in (9,9‘-disubstituted difluorenyl)(dimethyl) derivatives of group 14 elements Me2E(CR‘R2)(CR‘ ‘R2) (E = Si, R‘ = Me, R‘ ‘ = SiMe3, 6a; E = Ge, R‘ = Me, R‘ ‘ = SiMe3, 6b; and E = Sn, R‘ = R‘ ‘ = SiMe3, 5c; CR2 = fluorene units). This is in sharp contrast with the structure of monosubstituted Me2Ge(CHR2)(CR2-SiMe3) (3b) and disubstituted Me2E(CMeR2)2 (E = Ge, 4b; E = Sn, 4c) derivatives where the two fluorene units are almost perpendicular. Intramolecular C−H···π interactions are revealed by solution ¹H NMR spectroscopy and supported by the AM1 molecular orbital calculations. Intermolecular (aryl, alkyl)C−H···π interactions leading to supramolecular associations are shown by the crystal structures of 3b, 4b, 4c, 5c, and 6a. In 4b and 5c rather unusual CH···HC distances resembling the “dihydrogen” bonds are noticed. Synthesis, NMR spectra, and gas phase conformations predicted on the basis of AM1 semiempirical molecular orbital calculations are discussed for Me2E(CR‘R2)(CR‘ ‘R2) (E = Si, R‘ = R‘ ‘ = SiMe3, 5a; E = Ge, R‘ = R‘ ‘ = SiMe3, 5b; E = Sn, R‘ = H, R‘ ‘ = Me, 2c; R‘ = H, R‘ ‘ = SiMe3, 3c; R‘ = Me, R‘ ‘ = SiMe3, 6c; CR2 = fluorene units).

Tungsten hexaaryloxide complexes of formula W(OAr)6 (Ar = C6H5, 1; C6H4F-4, 2; C6H3F2-3,4, 3) have been synthesized by the reaction of W(O)Cl4 and ArOH in 22−28% yield. The complexes were characterized by ¹H, ¹³C, ¹⁹F, and ¹⁸³W NMR (1, δ = −474.8; 2, δ = −416.3; 3, δ = −446.3), melting point (1, 95 °C; 2, 101 °C; 3, 105 °C), IR, microanalysis, and single-crystal X-ray diffraction (octahedral coordination). Aerosol-assisted chemical vapor deposition of W(OAr)6 using acetone and toluene solvents and substrate temperatures from 300 to 500 °C produced blue tungsten oxide films on glass substrates. The films were analyzed by glancing angle powder diffraction and shown to be amorphous at 300 °C, but consisted of crystalline WO3-x at higher deposition temperature. Annealing the films from 1 at 550 °C in air for 30 min produced yellow γ-WO3 with preferred growth in the [020] direction. Raman analysis of the as-formed films showed WO3-x with evidence for W^V−W^VI paired ions. Annealed samples produced Raman patterns for γ-WO3 (807, 715, 273, and 133 cm^-1). The films were adhesive to the substrate, conformal, passed the Scotch tape test, and gave good coverage. Typical growth rates were 20−50 nm min^-1. SEM showed uniform films consistent with an island growth mechanism. Energy dispersive analysis confirmed the presence of only tungsten and oxygen. XPS showed that the as-formed films were WO3-x (x ≈ 0.22) with binding energy shifts for W 4f5/2 at 37.2 and 4f7/2 34.4 eV and for oxygen 1s at 532.6 eV. The as-formed films had an absorption maxima at 320−360 nm (dependent on film thickness) and an onset for absorption at 400 nm. Reflectance/transmission measurements produced interference fringes that enabled a calculation of film thickness. In general the films showed good transmission from 500 to 1000 nm (60%) and some reflectivity (ca. 20%) over the same region. After annealing, the absorption edge was pushed more into the visible and the films showed evidence for some scattering associated with haze. The blue WO3-x films showed negligible photocatalytic activity. The annealed, yellow WO3 films were active photocatalysts and readily destroyed an overlayer of stearic acid.

Attempts to isolate the bis-N-heterocyclic carbene complex Ru(AsPh3)(IMes)2(CO)H2 (IMes = bis(1,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene)) by crystallization with either ethanol or hexane yields instead the ethanol and water complexes Ru(IMes)2(CO)(EtOH)H2 (1) and Ru(IMes)2(CO)(H2O)H2 (2), respectively. Both multinuclear NMR spectroscopy and X-ray crystallography demonstrate that these two compounds are isostructural with a trans arrangement of the hydride ligands. Thermolysis of 1 results in decarbonylation of the bound ethanol ligand to yield Ru(IMes)2(CO)2H2 (3). Substitution of the coordinated solvent ligands in 1 or 2 occurs readily with p-ethoxyphenol to give Ru(IMes)2(CO)(HOC6H4-p-OEt)H2 (4), while treatment of 2 with 1-propanethiol affords the thiol complex Ru(IMes)2(CO)(HSCH2CH2CH3)H2 (8). Reaction of 8 with CO gives the thiolate hydride species Ru(IMes)2(CO)2(SCH2CH2CH3)H (9), whereas addition of CO to either 1 or 2 affords Ru(IMes)2(CO)3 (5). The hydroxy hydride complex Ru(IMes)2(CO)2(OH)H (6) has been isolated as an intermediate on the pathway from 2 to 5. Addition of CO2 or p-HO2CC5H4N to solutions of 2 yields the bicarbonate complex Ru(IMes)2(CO)(κ²-O2COH)H (10) and the isonicotinate species Ru(IMes)2(CO)(κ²-O2CC5H4N)H (11), respectively. Addition of CO to 10 affords Ru(IMes)2(CO)2(η¹-O2COH)H (7). Treatment of complex 2 with excess acetonitrile yields the N-imidoylimidato complex Ru(IMes)2(CO)(NH&dbd;C(CH3)N&dbd;C(CH3)O)H (12), which arises from the formal addition of two molecules of acetonitrile in head-to-tail fashion across the RuO−H bond. Compounds 1, 2, 6, 7, 8, 9, 11, and 12 have been structurally characterized by single-crystal X-ray diffraction.

Addition of Ag[closo-CB11H12] to [(PPh3)2RhCl]2 affords the new exopolyhedrally coordinated complex [(PPh3)2Rh(closo-CB11H12)] (1), which has been characterized by multinuclear NMR spectroscopy and X-ray crystallography. Using the less nucleophilic [closo-CB11H6Br6]^- anion afforded the arene-bridged dimer [(PPh3)(PPh2-η⁶-C6H5)Rh]2[closo-CB11H6Br6]2 (2) with poor compositional purity. However, with the new precursor complexes [(PPh3)2Rh(nbd)][Y] (Y = closo-CB11H12 (3), closo-CB11H6Br6 (4); nbd = norbornadiene) as starting materials, treatment with H2 affords 1 and 2 in good yield and compositional purity. Complex 2 has been characterized by multinuclear NMR spectroscopy and X-ray diffraction. The new complexes 3 and 4 have been evaluated as internal alkene hydrogenation catalysts using the substrates cyclohexene, 1-methylcyclohexene, and 2,3-dimethylbut-2-ene under the attractive conditions of room temperature and pressure. These new catalysts have also been compared with [(PPh3)2Rh(nbd)][BF4] and Crabtree's catalyst, [(py)(PCy3)Ir(cod)][PF6] (cod = 1,5-cyclooctadiene). A clear counterion effect is observed. For the hydrogenation of cyclohexene the [BF4]^- and [closo-CB11H12]^- salts are broadly similar, but the [closo-CB11H6Br6]^- salt is significantly better, matching Crabtree's catalyst in hydrogenation efficiency. This pattern is mirrored in the hydrogenation of 1-methylcyclohexene and the sterically hindered 2,3-dimethylbut-2-ene, although with the latter substrate Crabtree's catalyst does outperform 4. Nevertheless, these results are excellent for a rhodium complex, which have traditionally been considered as ineffectual catalysts for the hydrogenation of internal alkenes at room temperature and pressure. The deactivation product in the catalytic cycle, [(PPh3)2HRh(μ-Cl)2(μ-H)RhH(PPh3)2][CB11H12] (5), has been characterized by multinuclear NMR spectroscopy and X-ray crystallography.

The ruthenium complexes Ru(PPh3)3(CO)(C2H4) (1) and RuH(o-C6H4C(O)CH3)(L)(PPh3)2 (2, L = PPh3; 3, L = CO; 4, L = DMSO) have been prepared in order to assess their activity for catalyzing the insertion of alkenes into the ortho C−H bond of aromatic ketones (Murai reaction). Treatment of RuH2(CO)(PPh3)3 with ethene in refluxing toluene afforded 1, which has been characterized by multinuclear NMR spectroscopy and X-ray crystallography. Excess acetophenone reacted with Ru(H2)H2(PPh3)3 to give RuH(o-C6H4C(O)CH3)(PPh3)3 (2), which loses triphenylphosphine upon addition of CO or DMSO to give RuH(o-C6H4C(O)CH3)(CO)(PPh3)2 (3) and RuH(o-C6H4C(O)CH3)(DMSO)(PPh3)2 (4), respectively. The X-ray crystal structures of both of these compounds have been determined. The activity for catalyzing the reaction of 2‘-methylacetophenone with triethoxyvinylsilane follows the order RuH2(CO)(PPh3)3 > 2 > 1 > 4. Complex 3, along with both RuH2(CO)(AsPh3)3 and RuH2(CO)(dppp)(PPh3) (dppp = Ph2P(CH2)3PPh2), show essentially zero catalytic activity.

The high affinity of adenophostin A for 1d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors may be related to an alteration in the position of its 2‘-phosphate group relative to the corresponding 1-phosphate group in Ins(1,4,5)P3. To investigate this possibility, two bicyclic trisphosphates 9 and 10, designed to explore the effect of relocating the 1-phosphate group of Ins(1,4,5)P3 using a novel fused-ring system, were synthesized from myo-inositol. Biological evaluation of 9 and 10 at the Ins(1,4,5)P3 receptors of hepatocytes showed that both were recognized by hepatic Ins(1,4,5)P3 receptors and both stimulated release of Ca²⁺ from intracellular stores, but they had lower affinity than Ins(1,4,5)P3. This finding may be explained by considering the three-dimensional structures of 9 and 10 in light of recent studies on the conformation of adenophostin A.

Steroid sulfatases regulate the formation of estrogenic steroids which can support the growth of endocrine-dependent breast tumors. Therefore, the development of potent steroid sulfatase inhibitors could have considerable therapeutic potential. Several such inhibitors have now been developed including estrone 3-O-sulfamate (EMATE, 1), which shows potent active site-directed inhibition. However, EMATE was subsequently shown to be also a potent estrogen. In an attempt to reduce the estrogenicity while retaining the potent sulfatase inhibitory properties associated with this type of molecule, (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene (5) (estrone oxime 3-O-sulfamate, OMATE) was synthesized. The X-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene (4) (estrone oxime) demonstrated the presence of only one geometrical isomer [anti-isomer, (E)]. OMATE potently inhibited estrone sulfatase (E1-STS) activity and was similar to EMATE (>99% inhibition at 0.1 μM in MCF-7 breast cancer cells). It was also evaluated in vivo for its estrogenicity and ability to inhibit sulfatase activity. While it was equipotent with EMATE in vivo as a sulfatase inhibitor, it surprisingly had a stimulatory effect on uterine growth in ovariectomized rats about 1.5-fold greater than that of EMATE. Thus, OMATE possesses potential as a superestrogen and modification at C-17 is identified as a useful route for enhancement of estrogenicity in sulfamate-based estrogens.

Novel organoplatinum complexes of the enantiomerically pure P, N ligand, (4S)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-1,3-oxazoline, have been synthesized and shown to act as Lewis acids. These complexes consist of the bidentate P, N ligand, an achiral organic ligand, and a solvent ligand that can be readily displaced by organic substrates. The solvent ligand is situated cis to the nitrogen donor and, as such, is in a “chiral pocket” created by the oxazoline ring. The complexes are readily prepared from the well-known, and versatile, precursors (COD)PtR2 and are obtained as single isomers. Two of the complexes have had their structures elucidated by X-ray crystallography. The cationic complexes were shown to be enantioselective catalysts in the Michael reaction of α-cyano carboxylates with methyl vinyl ketone.

Treatment of all-cis-Ru(dppe)(CO)2Cl2 (dppe = Ph2PCH2CH2PPh2) with 2 equiv of AgOSO2CF3 yields the bis(triflate) complex Ru(dppe)(CO)2(OSO2CF3)2 (1), which has been characterized by NMR spectroscopy and X-ray crystallography. Exposure of solid 1 to atmospheric moisture gives the carbonyl aqua complex Ru(dppe)(CO)(H2O)(OSO2CF3)2 (2). The X-ray structure of 2 shows both intra- and intermolecular hydrogen bonding between the coordinated water and triflates. The ¹⁹F NMR spectra of 1 and 2 display coupling between the triflate groups; ¹⁹F−¹⁹F NOESY suggests that this arises from both through-bond and through-space coupling. The reaction of 1 with 10 equiv of water results in the rapid formation of a species assigned as the cationic diaqua complex [Ru(dppe)(CO)(H2O)2(OSO2CF3)][OSO2CF3] (3). Over a longer period of time, further reaction occurs to form the triaqua carbonyl complex [Ru(dppe)(CO)(H2O)3][OSO2CF3]2 (4), which has also been characterized by X-ray crystallography. The structure of 4 indicates that all three water ligands participate in hydrogen bonding. Complex 4 is unstable in the absence of water, re-forming a mixture of 1 and 2.