Julia M. Dickinson

Bioactive 4-substituted-6-methyl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines.

Bioactive synthetic 4-substituted-6-methyl-2-pyrones are reported. Various 4-substitutents have been incorporated using Pd-catalysed carbon-carbon bond coupling procedures. Preliminary screening of the 2-pyrones against human ovarian carcinoma (A2780) and human chronic myelogenous leukaemia (K562) cell lines show that 4-alkynyl-6-methyl-2-pyrones have excellent potential as anticancer agents. The pyrones demonstrate broad spectrum antimicrobial activities.

An efficient synthesis of 4-alkenyl/alkynyl-6-methyl-2-pyrones via Pd-catalysed coupling on 4-bromo-6-methyl-2-pyrone

We herein report the efficient syntheses of biologically active 4-alkenyl- and 4-alkynyl-6-methyl-2-pyrones using Pd-catalysed coupling procedures. A palladium on carbon/triphenylphosphine combination is shown to be the most effective catalyst for Sonogashira cross-coupling of several terminal acetylenes with 4-bromo-6-methyl-2-pyrone in yields of up to 95%.

Pd-catalysed cross coupling of terminal alkynes to diynes in the absence of a stoichiometric additive

An efficient, room temperature procedure for the cross-coupling of a range of terminal alkynes, using standard Sonogashira cross-coupling conditions (Pd/Cu) is presented. At higher reaction temperatures, head-to-tail or head-to-head dimerisation affords 1,3- and 1,4-disubstituted enynes, respectively as minor products.

Suzuki cross-coupling approaches to the synthesis of bioactive 3-substituted and 5-substituted-4-methoxy-6-methyl-2-pyrones

Suzuki cross-coupling has been used to access a wide range of 3- and 5-substituted 2-pyrones, which show remarkable inhibitory activity against bacteria, yeasts and fungi. 3-Octenyl and 5-octenyl 2-pyrones inhibit human ovarium carcinoma (A2780) and human chronic myelogenous leukaemia (K562) cell lines at the micromolar level.

Selenium dioxide E-methyl oxidation of suitably protected geranyl derivatives—synthesis of farnesyl mimics

Difunctional allylic terpenes are important synthetic building blocks. Functionalisation of protected geranyl derivatives by SeO2 provides a convenient route to such compounds. The effect of the geranyl protecting group on the oxidation of the terminal E-methyl group was systematically investigated.

Identification of novel mammalian squalene synthase inhibitors using a three-dimensional pharmacophore.

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerisation of farnesyl diphosphate in a [1-4] head to head fashion to form squalene, and is the first committed step in cholesterol biosynthesis. Specific inhibitors of squalene synthase would inhibit cholesterol formation and allow production of other important compounds derived from the cholesterol biosynthetic pathway, namely the ubiquinones (co-enzyme Q(10)), dolichol, and would also allow the isoprenylation process of ras by farnesyl-protein transferase. The construction of a hypothetical squalene synthase three-dimensional pharmacophore is presented. It serves as a template for the identification of several new potential classes of inhibitors. The synthesis, anti-microbial and mammalian pig liver squalene synthase activities of analogues based on the bicyclo[3.2.0]heptane and bicyclo[3.3.0]octane ring systems are reported. Analogues of the latter system are pro-drug type inhibitors and exhibit promising biological activity.

Synthesis and Antimicrobial Evaluation of Farnesyl Diphosphate Mimetics

The synthesis and first antimicrobial evaluation of farnesyl diphosphate mimetics are described. Several analogues (10, 12, 13, and 20) are inhibitors of Candida albicans, Shizosaccharomyces pombe, and Saccharomyces cerevisiae. The activities of analogues 10, 12, and 13, which contain a omega-phenyl moiety and a diphosphate isostere, are not attributable to inhibition of sterol biosynthesis via squalene synthase. Two geranyl phenylsulphones (14 and 15) are potent inhibitors of Escherichia coli. Analogue 15 exhibits potent activity towards Salmonella typhimurium and Pseudomonas aeruginosa (MIC-2 microg/mL) and represents the first type of semi-synthetic terpenoid allylic sulphone active against these bacteria.

Palladium-catalysed [π2a+π2s] cycloadditions of α-bromoalkyl ketenes to cyclopentadiene

Abstract 7-Substituted bicyclo[3.2.0]hept-2-en-6-one derivatives were identified as intermediates towards biologically interesting compounds. An improved synthesis of 7-alkyl-7-bromobicyclo[3.2.0]hept-2-en-6-ones by palladium-catalysed [ π 2a+ π 2s] cycloaddition of α-bromoalkyl ketenes to cyclopentadiene is described. Increased yields and increasing exo alkyl cycloadducts were observed with various palladium catalysts under standard dehydrochlorination conditions.

Influence of palladium(II) complexes on the cycloaddition of α-bromoalkyl ketenes to cyclopentadiene

Abstract Palladium(II) complexes, of the type PdL 2 X 2 and PdX 2 , influence both the yields and endo / exo ratio in formation of several 7-bromo-7-alkylbicyclo[3.2.0]hept-2-en-6-ones. Standard dehydrochlorination of α-bromoacyl chlorides with triethylamine in the presence of cyclopentadiene and palladium catalyst promotes the formation of the exo cycloadducts, which is accompanied by an improvement in the yields for both endo and exo cycloadducts. The mechanism of the palladium-mediated cycloaddition is discussed.