Frederick A. Luzzio

Thalidomide analogues: derivatives of an orphan drug with diverse biological activity

Introduced as a sedative during the late 1950s, the realisation of the potent human embryotoxicity of thalidomide led to its withdrawal from the market in early 1961. Although the drug was discontinued, its teratogenic properties attracted unceasing interest as evidenced by numerous reports over the years. As investigations into its teratogenicity continued, thalidomide was serendipitously found, in separate investigations, to be effective therapy for the symptoms of leprosy (erythema nodosum leprosum). Later, the compound was found to be active against the aphthous ulcers of Behcet’s syndrome and effective as a substitute for immunosuppressive therapy for graft-versus-host disease. The relevance of thalidomide in immunosuppressive therapy has also included ailments such as cachexia, HIV wasting and Crohn’s disease. Although reports dating from the mid 1990s have disclosed the antiangiogenic activity of thalidomide, its inhibition of TNF-α, together with its immunomodulatory properties and therapeutic effectiveness in multiple myeloma, have been fast gaining attention. Consequently, a number of synthetic and biological investigations have targeted analogues with higher potencies in several of the above-mentioned therapeutic areas, as well as having lower undesirable side effects. As a result, a number of interesting compounds of varied structure have been synthesised and tested for their ability to inhibit angiogenesis or act as immunosuppressant, immunomodulatory, anti-inflammatory or anticancer agents.

Alkylation and annulation of 3-(phenylsulfonyl)-2-alkyl-2,3-dihydroisoindol-1-ones

Abstract The hydroxylactams obtained from reduction of N-substituted phthalimides were phenylthiated and oxidized to give 3-(phenylsulfonyl)-2,3-dihydroisoindol-1-ones. Deprotonation of the sulfones with sodium hydride followed by treatment with electrophiles gave substitution. Sulfones with suitably-disposed α,β-unsaturated ester groups gave cyclic products from intramolecular Michael addition. Desulfurization of the phenylsulfonyl intermediates was effected in quantitative yield using Raney nickel promoted by ultrasound.

Synthetic studies directed toward the liposidomycins: Preparation and reactions of serine-derived epoxides

Summary The preparation of an oxiranyl serine derivative which will be incorporated into the diazepanone fragment of the liposidomycin B core subunit is described. Reactions of the epoxide with nitrogen nucleophiles afforded the 1,2-(O,N-protected)-4-N-functionalized-3-butanols in modest to good yields. A Mosher ester analysis of the alcohol resulting from azide promoted oxirane ring opening is also discussed.

A facile scheme for phthalimide ⇌ phthalimidine conversion

Desulfurization of phenylthiolactams using an ultrasound-promoted Raney nickel protocol yields the corresponding N-substituted phthalimidines. Benzylic oxidation of the N-substituted phthalimidines by treatment with 2, 2′-bipyridinium chlorochromatem-chloroperbenzoic acid (BPCC/MCPBA) affords the original phthalimides. Thereduction-desulfurization is applied to the preparation of a deoxythalidomide derivative which is a TNF-α inhibitor.

Annonacin in Asimina triloba fruit: Implication for neurotoxicity

INTRODUCTION The acetogenin, annonacin, from the tropical annonaceous plant Annona muricata, is a lipophilic, mitochondrial complex I inhibitor reported to be more toxic than rotenone to mesencephalic neurons. The temperate annonaceous plant Asimina triloba (pawpaw) is native to the Eastern United States and products are available online. This study determined whether annonacin is in the pawpaw fruit pulp and whether it or the crude ethyl acetate extract is toxic to cortical neurons. METHODS Pawpaw extract was prepared by pulp extraction with methanol and liquid-liquid partitioning with ethyl acetate (EtOAc). Annonacin was isolated from the crude EtOAc extract via column chromatography using a gradient solvent system of increasing polarity. Mass spectroscopy, nuclear magnetic resonance and infrared spectroscopy were used to compare isolated material with synthetic annonacin data and a natural annonacin sample. Toxicity of isolated annonacin and the total EtOAc extract was determined in primary rat cortical neurons using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS The average concentration of annonacin in the fruit pulp was 0.0701±0.0305mg/g. Purified annonacin (30.07μg/ml) and crude EtOAc extract (47.96μg/ml) induced 50% death of cortical neurons 48h post treatment. Annonacin toxicity was enhanced in the presence of crude extract. DISCUSSION Pawpaw fruit contains a high concentration of annonacin, which is toxic to cortical neurons. Crude fruit extract also induced neurotoxicity, highlighting the need for additional studies to determine the potential risks of neurodegeneration associated with chronic exposure to pawpaw products.

2,2′-Bipyridinium chlorochromate/m-chloroperbenzoic acid-mediated cleavage of cyclic acetals to hydroxyesters☆

Abstract Benzylidene acetals are cleaved to hydroxyesters by means of a reagent system composed of 2,2′-bipyridinium chlorochromate (BPCC) and m -chloroperbenzoic acid. Oxidative cleavage of a 4,6-O-benzylidene glucose derivative affords a 6-O-benzoyl derivative.

Efficient Preparation and Processing of the 4-Methoxybenzyl (PMB) Group for Phenolic Protection Using Ultrasound

Power ultrasound efficiently facilitates the rapid preparation and reaction of 4-methoxybenzyl chloride (PMB-Cl) 1 in providing protected phenolic ether intermediates for organic synthesis. Using two-phase systems in both the ultrasound-promoted preparation and reactions of PMB-Cl, typical runs produce PMB-protected products within 15 min. When compared with nonsonicated control reactions, the results demonstrate clear advantage in terms of efficiency when the protocol is applied to the mild and selective protection of various multisubstituted phenols including sensitive phenolic aldehydes.

Thalidomide metabolites and analogs. Part 2: Cyclic derivatives of 2-N-phthalimido-2S,3S (3-hydroxy) ornithine

Abstract E-(5-N-phthaloyl)-2-pentenoic acid benzyl ester was dihydroxylated by a Sharpless AD-mix protocol followed by mononosylation of the resultant 2R,3S diol. Azide displacement of the mononosylate followed by protection with the TBDMS group gave the e-N-phthaloyl-substituted-β-tert-butyldimethylsilyloxy-α-azidocarboxylic acid benzylester. Hydrazinolysis resulted in removal of the phthalimide group with concomitant lactamization to the 4-silyloxy-3-azidopiperidinones. Staudinger reduction of the azidopiperidinones followed by N-phthaloylation and hydrolysis of the silyl group afforded the 4′-hydroxylated-6′-deoxythalidomide derivatives.

The aluminum amalgam reduction of 2-nitroalkanols promoted by ultrasound

Abstract The sonochemical promoted aluminum amalgam reduction of 2-nitroalkanols provides an improved yield and accelerated conversion to the corresponding amino alcohols when compared to the nonultrasound (benchtop) reductions. The appearance of by-product hydroxylamines is minimized during the ultrasound promoted reaction. The product amino alcohols were conveniently acylated in situ with promotion by ultrasound thus affording the N-acyl derivatives in the same operation.

ORGANOMERCURY/ALUMINUM-MEDIATED ACYLATIVE CLEAVAGE OF CYCLIC ETHERS

Abstract Epoxides and tetrahydrofurans are cleaved with concomitant acylation to chloroalkyl esters using a reagent system composed of an organomercurial, aluminum metal and an acid chloride. The cleavage is promoted under mild conditions by a range of readily-available cyclic β-alkoxychloromercurials and acid chlorides. Using mainly tetrahydrofuran and cyclohexene oxide as substrates, the yield of isolated chloroesters ranged from 52 to 96%.