Asymmetric catalysis : ligand design and microwave acceleration

This thesis deals partly with the design and synthesis ofligands for use in asymmetric catalysis, and partly with theapplication of microwave heating on metal-based asymmetriccatalytic reactions. Enantiomerically pure pyridyl alcohols and bipyridylalcohols were synthesized from the chiral pool for future usein asymmetric catalysis. Lithiated pyridines were reacted withseveral chiral electrophiles, yielding diastereomeric mixturesthat could be separated without the use of resolutiontechniques. New pyridino- and quinolinooxazolines were synthesized andtested in palladium-catalyzed asymmetric allylation using1,3-diphenyl-2-propenyl acetate and dimethyl malonate. Theconformational preferences of the ligands in palladiumcomplexes were studied with crystallography, 2D-NMR techniquesand DFT calculations. Conclusions about how the chirality wastransferred from the ligand to the substrate could be drawnfrom the conformational analysis. The effect of heating Pd- and Mo-catalyzed asymmetricallylic substitution reactions was investigated with oil bathheating and microwave irradiation. With a few exceptions,ligands with high room temperature selectivity were shown toretain their selectivity on heating. Reaction rates, catalyststability and product selectivities of microwave-heatedreactions were compared with those of reactions performed inoil bath. Palladium-catalyzed asymmetric allylation was studied withseveral ligand types, allylic substrates and nucleophiles. Someof the experimental procedures had to be adapted to microwaveheating conditions. The procedure for asymmetric allylation catalyzed bybispyridylamide molybdenum complexes was developed into aone-pot microwave-mediated reaction. With microwaves, Mo(CO)6could be used as an easily-handled metal sourceand inert conditions could be omitted. Derivatives of thebispyridylamide ligandswere synthesized and tested withmolybdenum as catalysts to investigate the effects ofsubstituents on the pyridine ring. Keywords: ligand, asymmetric catalysis, pyridylalcohols, oxazolines, conformational study, Pd-allyl, fastchemistry, microwave chemistry, Mo-allyl, bispyridylamides.NR 2014080

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties. Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50. Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells. Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer

Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (<b>12</b>) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (<b>1</b>). A further scaffold modification to a (4-cyanophenyl)­glycinamide (e.g., <b>29a</b>) led to the development of compound <b>32</b>, with a <i>K</i>_d value of 32 nM and an EC₅₀ value of 0.67 μM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with <b>1</b> and represents a promising lead for further development

Iron chelators target both proliferating and quiescent cancer cells

Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells