Excretion balance and metabolism of the progestagen Org 30659 in healthy postmenopausal women

Metabolism of Org 30659 ((17alpha)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one), a new potent progestagen currently under clinical development by NV Organon for use in oral contraception and hormone replacement therapy, was studied in vivo after oral administration to healthy postmenopausal women. After oral administration of [14C]-Org 30659 to postmenopausal women, the compound was extensively metabolized. The dosed radioactivity was predominantly excreted via urine. Org 30659 was to a large extent metabolized at the C3- and the C17-positions. Phase II metabolism, and in particular conjugation with glucuronic acid at the 17beta-hydroxy group, is the major metabolic route for Org 30659 in vivo. Not only phase II metabolism was observed for Org 30659 after oral administration to postmenopausal volunteers, but also metabolism in the A-ring occurred, especially reduction of the 3-keto-Delta(4) moiety to give 3alpha-hydroxy, 5alpha(beta)-dihydro and 3beta-hydroxy, 5alpha-dihydro derivatives. Oxidative metabolism (6beta-hydroxylation) observed in human liver preparations in vitro, was not observed to a significant extent in vivo. So, in vitro human metabolism is different from the in vivo metabolism, indicating that the in vitro-in vivo extrapolation is far from straightforward, at least when only liver preparations are used. The proper choice of the in vitro system (e.g., microsomes, hepatocytes, slices or individually expressed enzymes) and the substrate concentration can be very important determinative factors for the predictability of the in vitro system for the in vivo situation. Species comparison of the metabolic routes of Org 30659 after oral administration indicated that the monkey seems to be a better representative species than the rat for the metabolism of Org 30659 in humans.     

Dialkyl-μ-ethylidene-μ-methylene-bis(pentamethylcyclopentadienyl)-dirhodium complexes: synthesis, spectra and decomposition reactions

The dialkyl-μ-ethylidene-μ-methylene-bis (pentamethylcyclopentadienyl)-dirhodium complexes [{(C₅Me₅)Rh}₂(μ-CH₂)(μ-CHMe) (R)₂] (4, P=Me; 5, Et; 6, n-Bu; 7, CH=CH₂; and 8, Z-CH=CHMe) have been prepared from RMgBr and [{(C₅Me₅)Rh}₂(μ-CH₂)(μ-CHMe)(X)₂] (2, X=Cl; 3, X=Br). Structures deduced from the NMR spectra show that the dialkyl complexes can exist in one trans and two cis forms. The decomposition of the dimethyl complex 4 is compared with that of the related di-μ-methylene complex; it reacts readily (30°C, MeCN solution) in the presence of one-electron oxidisers to give propene and methane and a little ethene and some butenes. Mass-spectrometric analysis of the ¹³C labelling in the organics originating from [{(C₅Me₅)Rh}₂(μ-CH₂)(μ-CHMe) (¹³CH₃)₂] shows that methane derives from the Rh---Me, ethene half from the ethylidene and half from coupling of Rh-methyl and a bridging methylene, while the propene arises almost entirely from the ethylidene and a rhodium methyl. The butenes come from coupling of ethylidene, methylene and a Rh-methyl, but only quite small amounts are formed; thus C+C coupling is the major decomposition path for the μ-ethylidenes, in contrast to the di-μ-methylene complexes where C+C+C coupling predominates. The divinyl complex [{(C₅Me₅)Rh}₂(μ-CH₂)(μ-CHMe) (CH=CH₂)₂] also underwent internal C+C coupling on reaction with AgBF₄ in MeCN to give a mixture of the allyl and methylallyl cations [(C₅Me₅)Rh(η³-CH₂CHCHR)(MeCN)]⁺(10, R=H; 11, R=Me).     

Chelated alkyl halide manganese complexes (η:η-C5H4CH2CH2X)Mn(CO)2 from photolysis of (η-C5H4CH2CH2X)Mn(CO)3

Manganese tricarbonyl complexes (η⁵-C₅H₄CH₂CH₂Br)Mn(CO)₃ (3) and (η⁵-C₅H₄CH₂CH₂I)Mn(CO)₃ (4), with an alkyl halide side chain attached to the cyclopentadienyl ligand, were synthesized as possible precursors to chelated alkyl halide manganese complexes. Photolysis of 3 or 4 in toluene, hexane or acetone-d₆ resulted in CO dissociation and intramolecular coordination of the alkyl halide to manganese to produce (η⁵:η¹-C₅H₄CH₂CH₂Br)Mn(CO)₂ (5) and (η⁵:η¹-C₅H₄CH₂CH₂I)Mn(CO)₂ (6). Low temperature NMR and IR spectroscopy established the structures of 5 and 6. Photolysis of 3 in a glass matrix at 91 K demonstrated CO release from manganese. Low temperature NMR spectroscopy established that the coordinated alkyl halide complexes are stable to approximately −20°C.     

On the reduction behaviour of 2-methoxyethyl and 2-methylthioethyl substituted zirconocene dichlorides: crystal structure of (η,σ-C5Me4CH2CH2S)2Zr

A reduction of previously reported 2-methoxyethyl and 2-methylthioethyl functionalized zirconocenedichlorides (η⁵-C₅Me₄CH₂CH₂EMe)(η⁵-C₅Me₅)(ZrCl₂ (E = O, S) and (η⁵-C₅Me₄CH₂CH₂EMe)(η⁵-C₅Me₄CH₂CH₂E′Me)ZrCl₂ (E = O, S; E′ = O, S) with Mg/Hg in THF leads unexpectedly to the products of O---Me and S---Me bond cleavage (η⁵,σ-C₅Me₄CH₂CH₂E)(η⁵-C₅Me₅)ZrMe (E = O, S), (η⁵,σ-C₅Me₄CH₂CH₂E)(η⁵-C₅Me₄CH₂CH₂E′Me)ZrMe (E = O, S; E′ = O), and (η⁵,σ-C₅Me₄CH₂CH₂S)₂Zr respectively. The crystal structure of (η⁵,σ-C₅Me₄CH₂CH₂S)₂Zr was established by X-ray analysis. At that same time the reduction of (ηsu5-C_{5Me4CH2CH2EMe)(η⁵-C5Me5)ZrCl2 (E> = O, S)} under 1 atm of CO gives either only the dicarbonyl derivative (η⁵-C₅Me₄CH₂CH₂EMe) (η⁵-C₆Me₅)Zr(CO)₂ (E = O) or a complex mixture of products (E = S).     

Design, synthesis and cytotoxic evaluation of keto-C-glycoside fatty acid conjugates.

Keto C-glycoside-fatty acid conjugates were synthesized from 6-hydroxy 2- and 4-keto unsaturated D-C-glycosides. These compounds were tested for cytotoxic activity against LFCl₂A cells (Rat hepatocarcinoma cells). The introduction of a lipid chain to 2-keto C-glycosides induced a drop in the cyctotoxic activity of these compounds. On the other hand 4-keto unsaturated C-glycoside-fatty acid conjugates possessed IC₅₀ values of 0.7–0.001 μM with 21 being the most potent.     

1,3-dithianes with acid functionalities: potent inhibitors and candidate affinity probes for the gaba-gated chloride channel

2 ,5 -1,3-Dithianes of the type (CH₃)C-CH(CH₂S)₂CH-C₆H₄-CC-R (R = CO₂H, CH₂CH₂CO₂H and CH₂CH₂PO₃H₂) are potent blockers of the GABA-gated chloride channel with 50% inhibition at 5–10 nM. Functionalization of the acid moieties provides candidate photoaffinity ligands [R = C(O)CHN₂ and CH₂CH₂C(O)CHN₂], affinity columns, and hapten-protein conjugates for antibody production.     

Synthesis and reactivity of early-late heterobimetallic complexes displaying a η-tantalum-alkylidene to palladium interaction

Tantalaalkylidene compounds, CHR=TaCl₃L₂ (R=^tBu or CMe₂Ph, L=THF or 1/2dimethoxyethane) mixed with the cyclopalladated dimer [Pd(2-C₆H₄CH₂NMe₂)(μ-Cl)]₂, 1, afford good yields of heterodimetallic complexes [Pd(2-C₆H₄CH₂NMe₂)(μ-Cl)(μ-CHR=TaCl₃L], 3a, 3b, in which the Ta=C unit is η²-interacting with the palladium atom, while a chloride ligand is bridging the tantalum and the palladium atoms. These compounds are fairly stable in air in the solid state and also in solution at RT. The interaction of the Ta=C unit with Pd in these bimetallic compounds is weak as shown by the ready formation of [Pd(2-C₆H₄CH₂NMe₂)PyCl] and CHR=TaCl₃Py₂ upon treatement with pyridine. Compounds analogous to 3a, b can also be obtained with 12 electrons tantalum complexes. Thus treating the same cyclopalladated dimer 1 with CHR=Ta(OAr)₃ (OAr=2,6-diisopropylphenyloxy) led to a much more stable though electron deficient species: [Pd(2-C₆H₄CH₂NMe₂)(μ-Cl)(μ-CH^tBu=Ta(OAr)₃], 3c. Substitution in 3a of one chloride ion by an alkyl group occurred at the tantalum metal via reaction with ZnR₂ (R=---CH₂CMe₂Ph) leading to [Pd(2-C₆H₄CH₂NMe₂)(μ-Cl)(μ-CH^tBu=TaCl₃(CH₂CMe₂Ph)], 4 for which there is no free rotation around the new Ta---C bond and in which one of the methylene protons is strongly interacting with the palladium centre. This compound is believed to mimic an intermediate to the formation of tantalacarbyne derivative, which was obtained earlier via reaction of the uncomplexed tantalacarbene compound with dialkylzinc compounds.     

Synthesis, solution behaviour and molecular structures of 16-electron closo-2-(Ph3P)-1-N,2-[μ-(η-CH2CH=Ch2)]-1-N-(σ-CH2CH=CH2)-2,1- RhCB10H10, the first η-olefinic monocarbon metallacarborane

The first η²-olefinic monocarbon metallacarbone closo-2-(Ph₃P)-1-N,2-[μ-(η²-CH₂CH=Ch₂)]-1-N-(σ-CH₂CH=CH₂)-2,1- RhCB₁₀H₁₀ has been prepared by the reaction of the dimeric anion {[Ph₃PRhB₁₀H₁₀CNH₂]₂-μ-H}⁻[PPN]⁺ with allyl bromide and characterized by a combination of spectroscopic methods and a single-crystal X-ray diffraction study. The variable temperature ¹H and ¹³C NMR studies revealed the fluxional behavior of the η²-olefinic complex in CD₂Cl₂ solution which is associated with the allyl side-chain exchange process.     

Reactions of the haloalcohols HO(CH2)nCl (n = 2, 3) with platinum(II) - alkynyl and -alkyne complexes. X-ray crystal structure of trans-[Pt(Me) {C(OCH2CH2Cl) (CH2Ph)} (PPh3)2] [BF4]

The chloro complexes trans-[Pt(Me)(Cl)(PPh₃)₂], after treatment with AgBF₄, react with 1-alkynes HC---C---R in the presence of NEt₃ to afford the corresponding acetylide derivatives trans-[Pt(Me) (C---C---R) (PPh₃)₂] (R = p-tolyl (1), Ph (2), C(CH₃)₃ (3)). These complexes, with the exception of the t-butylacetylide complex, react with the chloroalcohols HO(CH₂)_nCl (n = 2, 3) in the presence of 1 equiv. of HBF₄ to afford the alkyl(chloroalkoxy)carbene complexes trans-[Pt(Me) {C[O(CH₂)_nCl](CH₂R) } (PPh₃)₂][BF₄] (R = p-tolyl, N = 2 (4), N = 3 (5); R=Ph, N = 2 (6)). A similar reaction of the bis(acetylide) complex trans-[Pt(C---C---Ph)₂(PMe₂Ph)₂] with 2 equiv. HBF₄ and 3-chloro-1-propanol affords trans-[Pt(C---CPh) {C(OCH₂CH₂CH₂Cl)(CH₂Ph) } (PMe₂Ph)₂][BF₄] (7). T alkyl(chloroalkoxy)-carbene complex trans-[Pt(Me) {C(OCH₂CH₂Cl)(CH₂Ph) } (PPh₃)₂][BF₄] (8) is formed by reaction of trans-[Pt(Me)(Cl)(PPh₃)₂], after treatment with AgBF₄ in HOCH₂CH₂Cl, with phenylacetylene in the presence of 1 equiv. of n-BuLi. The reaction of the dimer [Pt(Cl)(μ-Cl)(PMe₂Ph)]₂ with p-tolylacetylene and 3-chloro-1-propanol yields cis-[PtCl₂{C(OCH₂CH₂CH₂Cl)(CH₂C₆H₄-p-Me}(PMe₂Ph)] (9). The X-ray molecular structure of (8) has been determined. It crystallizes in the orthorhombic system, space group Pna2₁, with a = 11.785(2), B = 29.418(4), C = 15.409(3) Å, V = 4889(1) ų and Z = 4. The carbene ligand is perpendicular to the Pt(II) coordination plane; the PtC(carbene) bond distance is 2.01(1) Å and the short C(carbene)-O bond distance of 1.30(1) Å suggests extensive electronic delocalization within the Pt---C(carbene)---O moietry.     

The nutrition of choline, carnitine, and related compounds in the blowfly, Phormia regina Meigen

Fifteen choline analogues were tested as substitutes for choline in the larval diet of Phormia regina. From the results the structural requirements for an adequate choline substitute are further defined. The choline analogue, (CH₃)₃+NCH₂CH₂CH₂OH, although not an inhibitor in the presence of choline, inhibits growth when choline is replaced in the diet by carnitine or γ-butyrobetaine. This compound presumably inhibits one of the reactions which metabolizes carnitine or γ-butyrobetaine to β-methyl choline.     

The synthesis and structures of tantalum complexes that contain a triamido or a diamidoamine ligand

Addition of (Me₃SiNHCH₂CH₂)₂NH (H₃[N₃(TMS)]) or (Me₃SiNH-o-C₆H₄)₂NH (H₃[ArN₃(TMS)]) to a solution of TaMe₅ yields [N₃(TMS)]TaMe₂ or [ArN₃(TMS)]TaMe₂, respectively. An X-ray study of [ArN₃(TMS)]TaMe₂ showed it to have an approximate trigonal bipyramidal structure in which the two methyl groups are in equatorial positions and the triamido ligand is approximately planar. Addition of (C₆F₅NHCH₂CH₂)₂NH (H₃[N₃(C₆F₅)]) to TaMe₅ yields first [(C₆F₅NCH₂CH₂)₂NH]TaMe₃, which then decomposes to [(C₆F₅NCH₂CH₂)₂N]TaMe₂. An X-ray study of [(C₆F₅NCH₂CH₂)₂N]TaMe₂ shows it to be approximately a trigonal bipyramid, but the C₆F₅ rings are oriented so that they lie approximately in the TaN₃ plane and two ortho fluorines interact weakly with the metal. Trimethylaluminum attacks the central nitrogen atom in [N₃(TMS)]TaMe₂ to give [(Me₃SiNCH₂CH₂)₂NAlMe₃]TaMe₂, an X-ray study of which shows it to be a trigonal bipyramidal species similar to the first two structures, except that the C-Ta-C bond angle is approximately 30° smaller (106.6(12)°). Addition of B(C₆F₅)₃ to [(C₆F₅NCH₂CH₂)₂NH]TaMe₃ yields {[(C₆F₅NCH₂CH₂)₂NH]TaMe₂}⁺ {B(C₆F₅)₃Me}⁻, the structure of which most closely resembles that of [(Me₃SiNCH₂CH₂)₂NAlMe₃]TaMe₂ in that the C-Ta-C angle is 102.0(6)°. The C₆F₅ rings in {[(C₆F₅NCH₂CH₂)₂NH]TaMe₂}⁺ are turned roughly perpendicular to the TaN₃ plane, i.e. ortho fluorines do not interact with the metal in this molecule.     

Synthesis and biological activity of cis-dichloro mono- and bis(platinum) complexes with N-alkyl-ethylenediamine ligands

Mono- and bis(platinum) complexes containing N-alkyl-ethylenediamine units of the type {cis-PtCl₂[H₂NCH₂CH₂NH(CH₂)_nCH₃]} (n=8, 9, 11, 15) and [{cis-PtCl₂(H₂NCH₂CH₂NH)}₂(CH₂)_n] (n=6, 8, 10, 12) and their corresponding dihydroxo-platinum(IV) complexes were synthesized. The structures of the metal chelates were derived from elemental analyses and their ¹H, ¹³C, IR spectra. The length of the aliphatic chains has been varied systematically, in order to increase the lipophilicity. Enlargement of the linker could also lead to more flexibility of one platinum sphere in reference to the attached DNA species. Using in vitro cytotoxicity tests it is shown that the biological activity of the bis(platinum) complexes increased, up to n=12, with the length of the linker. The longest linker in the ligands resulted in the most effective bis(platinum) complexes against L1210 murine leukemia cells.     

Metabolic switching patterns provide definitive evidence of substrate-specificity and delineate subtle differences in positioning at the aromatase active site [Poster 06]

We found that extensive metabolic switching can be triggered in aromatization. Up to 20–35% of (19-³H₃)-labeled substrate is diverted to non-estrogenic product, namely 1β- and 2β-hydroxy androgens, negating usefulness for [³H]water assays. The strikingly substrate-specific metabolite patterns observed reflect positioning at the active site, and the large kinetic isotope effects involved. This switching is unusual in that it involves: 1) tritium labeling, 2) a multistep enzymic process, and 3) the potential unraveling of an enzymic mechanism.     

Reactivity study of cyclopentadienyl osmium(II) bisphosphine azido complexes with activated alkynes and nitriles: Isolation of osmium triazolato and tetrazolato complexes by 1,3-dipolar addition

The cyclopentadienyl osmium(II) complexes [(η⁵-C₅H₅)Os(PPh₃)₂X] [X = Br (1), CH₃CN (2)] reacts with sodium azide (NaN₃) to yield the corresponding azido complex [(η⁵-C₅H₅)Os(PPh₃)₂N₃] (3). This undergoes [3+2] dipolar cycloaddition reaction with activated alkynes like dimethyl and diethyl acetylenedicarboxylate to yield triazolato complexes [(η⁵-C₅H₅)Os(PPh₃)₂{N₃C₂(CO₂R)₂}] [R = –CH₂CH₃ (4) and –CH₃ (5)]. The complex 3 also reacts with nitriles such as tetracyanoethylene (TCE), fumaronitrile and p-nitrobenzonitrile to yield complexes of the type [(η⁵-C₅H₅)Os(PPh₃)₂{N₄C₂(CN)C(CN)₂}] (6), [(η⁵-C₅H₅)Os(PPh₃)₂{N₃C₂HCN}] (7) and [(η⁵-C₅H₅)Os(PPh₃)₂{N₄C(C₆H₄–p-NO₂)}] (8). These complexes were fully characterized on the basis of microanalyses, FT-IR and NMR spectroscopic data. The molecular structure of the representative complex [(η⁵-C₅H₅)Os(PPh₃)₂{N₃C₂(CO₂CH₂CH₃)₂}] (4) was determined by single crystal X-ray analysis.     

Synthesis and incorporation of methyleneoxy(methylimino) linked thymidine dimer into antisense oligonucleosides

A convenient synthesis of a thymidine (T) nucleoside dimer (T-3′-CH₂-O-NCH₃-5′-T) 12 has been accomplished via a nucleoside coupling reaction. An alternative synthesis of 3′-deoxy-3′-C-hydroxymethylthymidine is described. The new dimer and methodology is useful for the development of backbone-modified antisense oligonucleosides.     

Synthesis, immobilization and catalytic activity of some silylated cyclopentadienyl rhodium(I) complexes

The mixture of isomers of silylated cyclopentadiene derivative C₅H₅CH₂CH₂Si(OMe)₃ (1) has been used for the syntheses of the mononuclear Rh(I) complexes [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(CO)₂ (3). [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(COD) (4) and [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(CO)(PPh₃) (5). Upon entrapment of 3–5 in silica sol-gel matrices, air stable, leach-proof and recyclable catalysts 6–8 resulted. Their catalytic activities in some hydrogenation processes were compared with those of the non-immobilized complexes 3–5, as well as with those of homogeneous and heterogenized non-silylated analogs, 9–14.     

Affinity probes for the GABA-gated chloride channel: 5e-tert-Butyl-2e-[4-(substituted-ethynyl)phenyl]-1,3-dithianes with photoactivatable, fluorescent, biotin, agarose and protein substituents

Affinity probes for the noncompetitive blocker or picrotoxinin site of the γ-aminobutyric acid (GABA)-gated chloride channel were designed for four types of applications: photoaffinity reagents to covalently label the binding site; fluorescent probes for receptor analysis; biotinylated compounds and agarose/sepharose conjugates for affinity chromatography; ligand-protein/enzyme conjugates for immunoassay. These 5e-tert-butyl-2e-[4-(substituted-ethynyl)phenyl]-1,3-dithianes were optimized by structure-activity studies for potency as inhibitors of ³H ethynylbicycloorthobenzoate binding to bovine brain membranes, measured as the concentration for 50% inhibition (IC₅₀). Preferred compounds are 5e-(CH₃)₃CCH(CH₂S)₂CH-2e-C₆H₄-4-CCCH₂OCH₂C(O)R, wherein R confers the following properties and 1C₅₀ values: R = SCH₂CH₂SCH₂C(O)C₆H₄-4-N₃, photo-affinity, 9 nM; R = NHCH₂CH₂NHC(O)C₆H₂-2-OH,5-1,4-N₃, photoaffinity, 105 nM; R = SCH₂CH₂S-4-benzofurazan-7-NO₂, fluorescent, 13 nM; R = SCH₂CH₂SCH₂-5-fluorescein, fluorescent, 27 nM; R = NHCH₂CH₂NH[C(O)(CH₂)₅NH]₂-biotin, affinity chromatography, 190 nM. The most potent photoaffinity ligand (IC₅₀ 9 nM) was labeled at 7 Ci mmol⁻¹ by reacting the appropriate thiol with ³H 4-azidophenacyl bromide (obtained by alumina-catalyzed tritium exchange of its enolizable hydrogens). The first steps have been taken in using the NCB site for affinity chromatography of the GABA_A receptor in CHAPS-solubilized bovine brain membranes with the dithiane-biotin probe and an avidin-acrylic bead system or with an analogous dithiane-agarose/sepharose column eluting with GABA or dithiane as above (R = OH). A protein conjugate of a related dithiane-monosulfone elicited production of specific antisera in rabbits. These findings illustrate the diversity and utility of new affinity probes prepared in the alkynylphenyldithiane series.     

metabolism of prostaglandins of the A-type

, originally introduced as an inadvertent contaminant in solutions used for evaluating the stability of prostaglandins, proved to lead to the rapid disappearance of the cyclopentenone unit of PGA₂ (as monitored by circular dichroic spectroscopy). The cyclopentenone unit is converted, in various metabolites, to a 9-keto, 9α or 9β-hydroxy group lacking the ring unsaturation. The major EtoAc-soluble 9-hydroxy metabolite (Compound-I) was shown to be 9α, 15α-dihydroxy-2,3,4,5-tetranor-13- -prostenoic acid. Similar tetranor 9-hydroxy metabolites with one additional degree of unsaturation, and with a 9β-hydroxy group, also occur but these have not been fully characterized. Only two of the wide range of 9-keto metabolites are fully characterized by mass spectral (MS) data: 9,15-oxo-2,3,4,5-tetranorprostanoic acid and 9,15-oxo-2,3,4,5-tetranor-13- -prostenoic acid. The water soluble metabolites have not been characterized further.The fully characterized metabolites together with MS data from mixtures of minor metabolites indicate that can perform the following transformations: β-oxidation, dehydrogenation at C-15, reduction of the enone carbon-carbon double bonds (both Δ^10,11 and Δ^13,14), reduction of the 9-ketone, and possibly migration of the cyclopentyl double bond (Δ^10,11 → Δ^11,12). metabolizes 15-epimeric PGA₂ equally readily with the production of similar products. PGA₁ affords less 9-keto metabolites with compound I constituting 33% of the product by HPLC analysis. displays some enantioselectivity, PGA₂ and 15-epi-PGA₂ are each metabolized more rapidly than their enantiomers. Other prostaglandins appear to be less readily metabolized.     

The metabolic fate of [H]estradiol in relation to dietary intake of boron in ovariectomized rats

It has been reported that boron (B) deprivation reversibly lowers plasma estradiol levels in postmenopausal women. In order to establish whether this reflects disturbances in the estrogen catabolic pathway and in particular in catechol estrogen metabolism, the influence of dietary B on the catabolism of [³H]estradiol-17β has been studied in ovariectomized rats. Rats were given diets containing <0.1 or 40 mg B.kg⁻¹, ovariectomized and then infused with [³H]estradiol-17β using osmotic pumps. Analysis of urine samples for conjugated, catechol and non-catechol estrogens did not reveal any effects of B on the recovery or the metabolic fate of tritium from the infused estradiol. These results do not therefore support the proposal that B influences estrogen catabolism by interacting with catechol estrogens.     

Misdirected π-donor ligands: (η-C5H5)2Zr(Cl) (SR) with sterically more demanding R groups have lower rotational barriers

Rotational barriers about the M-S bonds of 16-electron bent metallocene monothiolates (η⁵-C₅H₅)₂Zr(Cl) (SR) (R = −CH₃, −CH₂CH₃, −CH(CH₃)₂, −C(CH₃)₃) (1a–d) have been measured by dynamic ¹H NMR methods: 32, 33, 35 and 26 kJ mol⁻¹, respectively. The ground-state orientation about the Zr-S bonds of 1 that maximizes Spπ → Mdπ bonding (Cl-Zr-S-R ≈ 90°) also maximizes CpR steric interaction, whereas the rotational transition-state orientation (Cl-Zr-S-R ≈ 0°) is one that minimizes Spπ → Mdπ bonding and maximizes ClR steric interaction. Deviation from a ground-state orientation that is ideal for Spπ → Mdπ bonding might be expected as the size of the R group and CpR steric interaction increases. Thus, the aberrant trend for the R = −C(CH₃)₃ derivative could be attributed to a ground-state steric effect where the sterically demanding −C(CH₃)₃ group forces an unfavorable (misdirected) orientation for Mdπ-Spπ bonding, but a favorable orientation with respect to CpR and ClR steric interactions. However, the solid-state structures of (η⁵-C₅H₅)₂Zr(SR)₂ (R = −CH₃, −CH₂CH₃, −CH(CH₃)₂, −C(CH₃)₃) (2a–d) exhibit regular variation of their metric parameters as evidenced by their Zr-S-C bond angles of 108, 109, 113, and 124° and S-Zr-S′ bond angles of 97, 99, 100 and 106°, respectively. Neither the S′-Zr-S-R torsion angles nor the dihedral angles that describe the relationship between the S/Zr/S′ and Cp(centroid)/Zr/Cp′ (centroid) planes (both indicators of the relative orientation of the Zr dπ acceptor orbital and the thiolate S pπ donor orbital) reflect the steric demand of the R group. Thus, the size of the R group imposes a measured effect on the geometry of 2 and the tert-butyl group is not extraordinary. Although the enthalpic and entropic effects could not be deconvoluted for rotation about the Zr-S bond of 1 in the present study, literature precedents suggest that both enthalpic and entropic effects may play a role in determining the irregular trend that is observed.