Timothy J. Woodman

Microemulsion formulations for the transdermal delivery of testosterone

The objective was to develop a microemulsion formulation for the transdermal delivery of testosterone. Microemulsion formulations were prepared using oleic acid as the oil phase, Tween20 as a surfactant, Transcutol as cosurfactant, and water. The microemulsions were characterized visually, with the polarizing microscope, and by dynamic light scattering. In addition, the pH, conductivity (sigma) and viscosity (eta) of the formulations were measured. Moreover, differential scanning calorimetry and diffusion-ordered nuclear magnetic resonance spectroscopy were used to study the formulations investigated. Conductivity measurements revealed, as a function of the weight fraction of the aqueous phase, the point at which the microemulsion made the transition from water-in-oil to bicontinuous. Alterations in the microstructure of the microemulsions, following incorporation of testosterone, have been evaluated using the same physical parameters (pH, sigma and eta) and via Fourier-transform infrared spectroscopy (FT-IR), (1)H NMR and (13)C NMR. These methods were also used to determine the location of the drug in the colloidal formulation. Finally, testosterone delivery from selected formulations was assessed across porcine skin in vitro in Franz diffusion cells. The physical parameter determinations, combined with the spectroscopic studies, demonstrated that the drug was principally located in the oily domains of the microemulsions. Testosterone was delivered successfully across the skin from the microemulsions examined, with the highest flux achieved (4.6+/-0.6microgcm(-2)h(-1)) from a formulation containing 3% (w/v) of the active drug and the composition (w/w) of 16% oleic acid, 32% Tween20, 32% Transcutol and 20% water. The microemulsions considered offer potentially useful vehicles for the transdermal delivery of testosterone.

Lanthanide(III)chloride-tetrahydrofuran solvates: structural patterns within the series LnCl3(THF)n, where n = 2,3,3.5 and 4: crystal and molecular structures of [PrCl(μ-Cl)2(THF)2]n, [Nd(μ-Cl)3(H2O)(THF)]n and GdCl3(THF)4

Abstract Praseodymium(III), neodymium(III) and gadolinium(III) chloride adducts with tetrahydrofuran (THF) have been prepared and structurally characterized by X-ray crystallography. Removal of water from the corresponding hexahydrate LnCl3(H2O)6 using thionyl chloride in the presence of excess THF provides light-green cubic crystals of [PrCl3(THF)2]n (1), blue block crystals of [NdCl3(H2O)(THF)]n (2) and colourless needle crystals of GdCl3(THF)4 (3). In 1 each praseodymium atom is seven-coordinate and is linked to (two) adjacent metal centres by double (μ-Cl)2 halogen bridging units, resulting in a polymeric chain structure. The metal geometry approximates to distorted pentagonal bipyramidal with PrClbridge 2.852(6)–2.891(5), PrClterminal 2.668(6), PrOTHF 2.51(1) (axial), 2.53(2) A (equatorial). In 2 the structure is a two-dimensional cross-linked polymer in which each neodymium atom is connected to (three) others via double (μ-Cl)2 halogen bridge bonds. he coordination sphere of each metal centre comprises six chlorine atoms [NdClbridge 2.816(3)–2.938(3) A] and two oxygen atoms belonging to a THF molecule [NdO, 2.548(6) A] and a water molecule [NdO, 2.490(7) A], respectively. Hydrogen bonding interactions involving halogen atoms and coordinated water molecules from adjacent metal units (intermolecular) are observed, OH3·Cl 3.147–3.350 A. In 3 the molecular structure is based on a seven-coordinate pentagonal bipyramidal metal geometry in which two chlorides occupy the axial positions with the other chloride and the four solvate (THF) molecules making up the equatorial plane. GdCl 2.60(2)–2.66(2), GdO 2.40(2)–2.52(3) A. In addition, general comments concerning structural relationships within the series LnCl3(THF)n, where n = 2, 3, 3.5 and 4, are discussed.

α-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S

α-Methylacyl-CoA racemase (AMACR; P504S) catalyzes a key chiral inversion step in the metabolism of branched-chain fatty acids, ibuprofen and related drugs. Protein levels are increased in all prostate and some other cancer cells and it is used as a marker (P504S). The enzyme requires no cofactors and catalyzes its reaction by a stepwise 1,1-proton transfer via an enolate intermediate. The biological role of AMACR in cancer is complex, linking lipid metabolism with nuclear receptor (e.g. FXR and PPAR) activity and expression of enzymes such as cyclooxygenase-2 (COX-2). The roles of the various splice variants and the effects of single-nucleotide polymorphisms (SNPs) in cancers are discussed. A number of rationally designed AMACR inhibitors have been reported in the literature as potential cancer treatments. The opportunities and challenges for development of acyl-CoA esters as inhibitors are discussed from a medicinal chemical viewpoint. Other challenges for drug development include the problems in assaying enzymatic activity and the prediction of structure-activity relationships (SAR). Inhibitors of AMACR have potential to provide a novel treatment for castrate-resistant prostate cancers but this potential can only be realized once the biology is well understood. Recent work on the role of AMACR in parasitic diseases is also reviewed.

Role of B(C 6 F 5 ) 3 in catalyst activation, anion formation, and as C 6 F 5 transfer agent* , **

The versatile reactivity of B(C6F5)3 in alkene polymerization reactions is summarized. Adduct formation with basic anions such as CN– and NH2– gives extremely weakly co- ordinating diborates, which are the basis of some of the most active polymerization catalysts known to date. By contrast, the reaction of B(C6F5)3 with zirconium half-sandwich complexes leads to extensive C6F5 transfer, including the surprising formation of borole-bridged triple decker complexes. Main group alkyls undergo such C6F5 exchange reactions very readily unless donor ligands are present. Borate salts of new three-coordinate zinc alkyl cations proved to be highly effective catalysts for the ring-opening polymerization of epoxides and lactones.

Applications of NMR in the characterization of pharmaceutical microemulsions

Microemulsions have successfully proven themselves as useful vehicles for drugs through the different routes of administration because they can confer on drugs greater water solubility and bioavailability. The ability to understand the structural aspects of these important drug delivery systems is essential to the progress of this science. The use of NMR techniques in pharmaceutical and drug delivery science is increasing especially in the characterization field. This review demonstrates the major and novel NMR methods and techniques used in understanding and characterizing the different microemulsion components, types and structures.

Synthesis, Characterization, and Reactivity of Lanthanide Complexes with Bulky Silylallyl Ligands

The synthesis of new lanthanide allyl complexes of enhanced stability and solubility in saturated hydrocarbons based on silyl-substituted allyl ligands is reported. Thus the potassium salt K(CH2CHCHSiMe3) ( 1 ) reacts with YCl3 in tetrahydrofuran to give the tris-allyl complex Y(CH2CHCHSiMe3)3 ( 2 ), while K(CH2CHCHSiMe2tBu) ( 3 ) affords Y(CH2CHCHSiMe2tBu)3(THF)1.5 ( 4 ). Slow re-crystallization of 4 from light petroleum in the presence of tert-butylcyanide led to multiple insertion to give the sec-amido complex Y{NHC(tBu)(CH)3SiMe2tBu}2{?2-NHC(tBu)CH=CHCH2SiMe2tBu)CH(CHCHSiMe2tBu)CtBuNH}(THF)·(CH3CH(Me)(CH2)2CH3) ( 5 ), which was crystallographically characterized. The reaction of ScCl3(THF)3 with two equivalents of Li{1,3-C3H3(SiMe3)2} in tetrahydrofuran gives the bis-allyl complex {1,3-C3H3(SiMe3)2}2Sc(µ-Cl)2Li(THF)2 ( 6 ), while the analogous reaction of K{1,3-C3H3(SiMe3)2} ( 7 ) with either LaCl3 or YCl3 in tetrahydrofuran affords the bis-allyl complexes MCl{1,3-C3H3(SiMe3)2}2(THF)x (8, M = La, x = 1; 9, M = Y, x = 0). An attempt to prepare the similar neodymium complex gave the mono-allyl complex NdI2{1,3-C3H3(SiMe3)2}(THF)1.25 ( 10 ). The reactions of 8 and 9 with triisobutyl aluminum in benzene-d6 show allyl exchange between lanthanide and aluminum. Complexes 8 , 9 , and 10 have been tested with a variety of activator systems as catalysts for the polymerization of 1,3-butadiene.

N3-alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides.

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N(3). 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N(3)-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N(3)-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N(3)-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.

Structural characterization of the acetonitrile complex NbCl5(MeCN)

Abstract The monosolvate (MeCN) of niobium(V) chloride has been structurally characterized. The metal is six coordinate with a somewhat distorted octahedral geometry in which the four equatorial chlorine atoms are coplanar but are clearly bent towards the bound axial acetonitrile ligand, mean N ax NbCl eq 83.62(12)°. The NbCl bond distances lie in the range 2.249(2)–2.319(2) A and the metal to ligand distance, NbN, is 2.236(4) A.

Reactions of ZrOCl2·8H2O with carboxylic acids and thionyl chloride: crystal and molecular structures of K4[Zr(mal)4]·2H2O and K4[Zr(dipic)3]2·13.5H2O

Reactions of ZrOCl2·8H2O in aqueous solution with a carboxylic acid in the presence of K2CO3 have been studied as a route to ZrIV-carboxylates. With malonic acid (HO2CCH2CO2H) (H2mal) the product has been identified as K4[Zr(mal)4]·2H2O (1) by X-ray crystallography. The individual eight-coordinate zirconium anions contain four bidentate (OO′) malonate anions with the metal geometry approximating to a square antiprism with each chelating ligand spanning the two square faces, Zr—O 2.091(3)–2.288(3) Å. The four potassium cations feature irregular coordination spheres of oxygen atoms [from both H2O and (mal) ligand molecules] with a 7–9 coordination range. With 2,6-dicarboxypicolinic␣acid (HO2CC5NH3CO2H) (H2dipic) the product has been characterised as K4[Zr(dipic)3]2·13.5H2O (2) following X-ray diffraction studies. The structure consists of two [Zr(dipic)3]2- anions, four potassium cations and lattice solvate (H2O) molecules. Individual anions feature nine-coordinate zirconium in which each dipic ligand is terdentate, being bonded via one N (pyridine) and two O (carboxylate) atoms. The metal geometry approximates to tricapped trigonal prismatic with each nitrogen atom capping a regular face of four oxygen atoms, Zr—O, 2.216(6)–2.261(6) Å; Zr—N, 2.343(8)–2.361(7) Å. The potassium cations show similar environments to those observed in structure (1). Dehydration of ZrOCl2·8H2O using SOCl2 in the presence of an excess of THF effects removal of coordinated H2O molecules and hydroxy bridging groups to provide the anhydrous bis-adduct ZrCl4(thf)2 in good yield (72%).

3-Hydroxybenzene 1,2,4-Trisphosphate, a Novel Second Messenger Mimic and unusual Substrate for Type-I myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase: Synthesis and Physicochemistry

3‐Hydroxybenzene 1,2,4‐trisphosphate 4 is a new myo‐inositol 1,4,5‐trisphosphate analogue based on the core structure of benzene 1,2,4‐trisphosphate 2 with an additional hydroxyl group at position‐3, and is the first noninositol based compound to be a substrate for inositol 1,4,5‐trisphosphate 5‐phosphatase. In physicochemical studies on 2, when three equivalents of protons were added, the 31P NMR spectrum displayed monophasic behaviour in which phosphate‐1 and phosphate‐2 behaved independently in most of the studied pH range. For compound 4, phosphate‐2 and phosphate‐4 interacted with the 3‐OH group, which does not titrate at physiological pH, displaying complex biphasic behaviour which demonstrated co‐operativity between these groups. Phosphate‐1 and phosphate‐2 strongly interacted with each other and phosphate‐4 experienced repulsion because of the interaction of the 3‐OH group. Benzene 1,2,4‐trisphosphate 2 is resistant to inositol 1,4,5‐trisphosphate type I 5‐phosphatase catalysed dephosphorylation. However, surprisingly, 3‐hydroxybenzene 1,2,4‐trisphosphate 4 was dephosphorylated by this 5‐phosphatase to give the symmetrical 2,3‐dihydroxybenzene 1,4‐bisphosphate 16. The extra hydroxyl group is shown to form a hydrogen bond with the vicinal phosphate groups at −15 °C, and 1H NMR titration of the ring and hydroxyl protons in 4 shows the OH proton to be strongly stabilized as soon as the phosphate groups are deprotonated. The effect of the phenolic 3‐OH group in compound 4 confirms a critical role for the 6‐OH group of the natural messenger in the dephosphorylation mechanism that persists even in radically modified analogues.