Damon Donald Ridley

Preparation of stable, camphor-derived, optically active allylic sulfoxides

Abstract (+)-Camphor has been stereospecifically converted in three steps into a single isoborneol allyl sulfoxide derivative, which upon heating to 145° is quantitatively converted into its sulfoxide epimer; the anions of these compounds undergo stereospecific conjugate addition to cyclopent-2-en-1-one.

Metabolism of methandrostenolone in the horse: a gas chromatographic-mass spectrometric investigation of phase I and phase II metabolism

The phase I and phase II metabolism of the anabolic steroid methandrostenolone was investigated following oral administration to a standardbred gelding. In the phase I study, metabolites were isolated from the urine by solid-phase extraction, deconjugated by acid catalysed methanolysis and converted to their O-methyloxime trimethylsilyl derivatives. GC-MS analysis indicated the major metabolic processes to be sequential reduction of the A-ring and hydroxylation at C6 and C16. In the phase II study, unconjugated, beta-glucuronidated and sulfated metabolites were fractionated and deconjugated using a combination of liquid-liquid extraction, enzyme hydrolysis, solid-phase extraction and acid catalysed methanolysis. Derivatization followed by GC-MS analysis revealed extensive conjugation to both glucuronic and sulfuric acids, with only a small proportion of metabolites occurring in unconjugated form.

Citation searches in on-line databases: possibilities and pitfalls

Until recently the main source of scientific journal citations was the science citation index, which is now available in print and electronic formats. Searches in the electronic format were performed mainly by information professionals, but with the introduction of citations in the chemical abstracts service bibliographic database and the acceptance of the Web of Science as a means to access citations, many scientists and managers are searching directly for citation data. For comprehensive results the most reliable method is to use search terms based on first-listed authors of each publication, but this may be very time consuming. Electronic sources provide search algorithms which fast-track the process, but it is important that users understand the issues and how these algorithms work if reasonably reliable data are to be obtained.

Equine Metabolites of Norethandrolone: Synthesis of a Series of 19-Nor-17α-pregnanediols and 19-Nor-17α-pregnanetriols

A range of 19-nor-17α-pregnanediols and 19-nor-17α-pregnanetriols have been synthesized and used to confirm the structures of major equine urinary metabolites of the synthetic anabolic steroid norethandrolone (1). 19-Nor-5α,17α-pregnane-3α,17β-diol (2), 19-nor-5α,17α-pregnane-3β,17β-diol (4), 19-nor-5β,17α-pregnane-3α,17β-diol (6), and 19-nor-5β,17α-pregnane-3β,17β-diol (7) were prepared by stereoselective reduction of the 3-ene-4-one of norethandrolone. The 19-nor-5α,17α-pregnane-3β,16α,17β-triol (8) and 19-nor-5α,17α-pregnane-3β,16β,17β-triol (9) were prepared from 19-nortestosterone (11) by multistep processes in which the critical step involved Grignard additions to 16-acetoxy-17-ones. The triols (20R)-19-nor-5α,17α-pregnane-3β,17β,20-triol (22) and (20S)-19-nor-5α,17α-pregnane-3β,17β,20-triol (23) were prepared from norethindrone (24) by initial selective A-ring reduction, then subsequent modification of the 17-ethynyl group. By comparison of these compounds with post-administration equine urine samples it was possible to establish A-ring reduction with 3β,5α stereochemistry as well as non-stereospecific 16-hydroxylation and 20-hydroxylation as significant metabolic pathways affecting norethandrolone in the horse.

Pharmacological evaluation of (S)-8-[123I]iodobretazenil: A radioligand for in vivo studies of central benzodiazepine receptors

In vitro studies on cortical membranes indicated (S)-8-[(123)I]iodobretazenil bound saturably to a single population of binding sites (B(max) = 2.33 pmol/mg protein) with a dissociation constant K(d) = 1.9 nM. (R)-8-[(123)I]Iodobretazenil displayed only non-specific binding. In vivo biodistribution of (S)-8-[(123)I]iodobretazenil in rats indicated high accumulation in regions of high BZR density. Radioactivity was blocked by preadministration with iodobretazenil and flumazenil, while non-BZR drugs had no effect on the uptake of activity in any brain region. (S)-8-[(123)I]Iodobretazenil uptake was saturable in a dose dependent manner (ID(50) = 0.13 mg/kg) in all brain regions. With the (R)-enantiomer no specific uptake was observed. Metabolite studies at 1-3 h p.i. indicated that greater than 95% of activity extracted from brain tissue corresponded to unchanged radiotracer while that in plasma was over 70%. (S)-8-[(123)I]Iodobretazenil potently and selectively labels BZR in vivo and deserves further investigation as a possible SPECT radiotracer.

Synthesis of Equine Metabolites of Anabolic Steroids: Reformatsky Reactions on Estran-17-ones

Reformatsky reactions involving ethyl bromoacetate/zinc are reported for 19-norandrosterone acetate and 19-norepiandrosterone acetate. In each case the major product was the 17β-alcohol from α-attack, although a significant amount of the 17α-alcohol from β-attack was also isolated. The ethyl 3-acetoxy-17β-hydroxy-19-nor-5α,17α-pregnan-21-oates were then hydrolysed to 3,17β-dihydroxy-19-nor-5α,17α-pregnan-21-oic acids or reduced to 19-nor-5α,17α-pregnane-3,17β,21-triols. Comparison of the synthetic products with compounds previously reported as metabolites of norethandrolone in the horse provided valuable information on the regio- and stereo-chemistry of equine steroid metabolism.

Methoxylated gramine derivatives from Phalaris aquatica

Abstract 7-Methoxygramine and 5,7-dimethoxygramine were isolated from the roots of 12-day-old seedlings of Phalaris aquatica . The structures were elucidated by spectroscopic methods. 5-Methoxygramine also was detected by TLC. All three gramine derivatives are reported for the first time.

Nitrogen versus oxygen group protection in hydroxypropylbenzimidazoles

In order to convert 1′H-benzimidazol-2′-ylpropanols into aryl ethers using Mitsunobu coupling, it was necessary to protect the benzimidazole nitrogen in the starting alcohols. Selective protection at nitrogen was achieved through N-benzyl derivatives, but attempts to protect the nitrogen directly through tert-butoxycarbonyl, acetyl, trityl, or tetrahydropyranyl derivatives were complicated either by selective reactions at oxygen or by the formation of bis-protected compounds. Transformations of some oxygen-protected derivatives are discussed, and in particular the conversion of the acetates of 1′H-benzimidazol-2′-ylpropanols to N-tetrahydropyranyl derivatives is described. Mitsunobu coupling involving the N-benzyl and N-tetrahydropyranyl derivatives and methyl 4-hydroxybenzoate were achieved, and thus afforded synthetic routes to the desired propylbenzimidazole aryl ethers.

Synthesis and evaluation of [123I]labelled analogues of the partial inverse agonist Ro 15-4513 for the study of diazepam-insensitive benzodiazepine receptors

The imidazobenzodiazepines ethyl 8-iodo-5,6 dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4] benzodiazepine-3-carboxylate 1 and tert-butyl 8-iodo-5,6 dihydro-5-methyl-6-oxo-4H-imidazo [1,5a][1,4] benzodiazepine-3-carboxylate 2 were prepared to study the diazepam-insensitive (DI) benzodiazepine receptor (BZR) subtype. The [123I] analogues were prepared via iododestannylation reactions in radiochemical yields of 70-80% and a specific activity >2,500 Ci/mmol. The tert-butyl analogue [123I]-2 exhibited nanomolar affinity for BZRs in homogenate membranes of rat cerebellum with Kd values for the diazepam-sensitive (DS) and DI receptors of 3.18 +/- 0.58 and 13.55 +/- 2.72 nM, respectively. The Bmax for cerebellar DS and DI receptors were 1,276 +/- 195 and 518 +/- 26 fmol/mg protein, respectively.

The Challenges with Substance Databases and Structure Search Engines

Structure connection tables, which are commonly used for the representation of chemical structures in electronic databases, are valuable for substances where specific valence bond structures are known or can be drawn. How-ever there are many classes of substances (for example alloys, catenanes, polymers, or salts) which cannot be fully represented by valence bond structures. There are also issues of definition (such as when a substance is a co-ordination compound, or hydrate, or salt), and of bonding types (resonance, donor complexes, π-complexes). Producers of chemical substance databases may address these issues in different ways and generally need to introduce concepts (for example multicomponent substances) with which chemical scientists may not be familiar. In addition to these aspects of database content, the searcher needs to understand the algorithms behind the structure search engines. For example, the SciFinder search engine has considerable in-built chemical intelligence at the initial search level and then has many tools to mine the data once obtained; the CrossFire search engine also employs several algorithms by default and allows further options to vary them.