(N-Heterocyclic Carbene)₂‑Pd(0)-Catalyzed Silaboration of Internal and Terminal Alkynes: Scope and Mechanistic Studies

Pd­(ITMe)₂(PhCCPh) acts as a highly reactive precatalyst in the silaboration of terminal and internal alkynes to yield a number of known and novel 1-silyl-2-boryl alkenes. Unprecedented mild reaction temperatures for terminal alkynes, short reaction times, and low catalytic loadings are reported. During mechanistic studies, <i>cis</i>-Pd­(ITMe)₂(SiMe₂Ph)­(Bpin) was directly synthesized by oxidative addition of PhMe₂SiBpin to Pd­(ITMe)₂(PhCCPh). This represents a very rare example of a (silyl)­(boryl)palladium complex. A plausible catalyst decomposition route was also examined

Synthesis of Oxindole-Based Bioorganometallic Kinase Inhibitors Incorporating One or More Ferrocene Groups

A series of oxindole-containing ferrocenes has been synthesized, studied in the solid state by X-ray crystallography, and tested for in vitro kinase inhibition. Many compounds show low or submicromolar activities against DYRK isoforms and VEGFR2, which in certain cases have been rationalized by molecular docking studies

Synthesis of Oxindole-Based Bioorganometallic Kinase Inhibitors Incorporating One or More Ferrocene Groups

A series of oxindole-containing ferrocenes has been synthesized, studied in the solid state by X-ray crystallography, and tested for in vitro kinase inhibition. Many compounds show low or submicromolar activities against DYRK isoforms and VEGFR2, which in certain cases have been rationalized by molecular docking studies

Targeting Epidermal Growth Factor Receptor with Ferrocene-Based Kinase Inhibitors

A series of ferrocene analogues based on a 6,7-dimethoxy-<i>N</i>-phenylquinazolin-4-amine template has been synthesized, and two compounds were characterized in the solid state by X-ray crystallography. The compounds have been tested for in vitro anticancer activity, against epidermal growth receptor (EGFR), and submicromolar IC₅₀ values have been determined

Comparison of the Reactivity of the Low Buried-Volume Carbene Complexes (ITMe)₂Pd(PhCCPh) and (ITMe)₂Pd(PhNNPh)

The novel Pd(0)-azobenzene complex (ITMe)₂Pd­(PhNNPh) (<b>5</b>) (ITMe = 1,3,4,5-tetramethylimidazol-2-ylidene) has been isolated and characterized in the solid state and by cyclic voltammetry. Its reactivity toward E–E′ bonds (E, E′ = Si, B, Ge) has been compared with that of the known carbene complex (ITMe)₂Pd­(PhCCPh) (<b>2</b>). Whereas <b>2</b> reacts with all E–E′ bonds studied, <b>5</b> only reacted with B–B and B–Si moieties, echoing our previous catalytic studies on azobenzenes

Inactivation of Fructose-1,6-Bisphosphate Aldolase Prevents Optimal Co-catabolism of Glycolytic and Gluconeogenic Carbon Substrates in <i>Mycobacterium tuberculosis</i>

<div><p>Metabolic pathways used by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) to establish and maintain infections are important for our understanding of pathogenesis and the development of new chemotherapies. To investigate the role of fructose-1,6-bisphosphate aldolase (FBA), we engineered an <i>Mtb</i> strain in which FBA levels were regulated by anhydrotetracycline. Depletion of FBA resulted in clearance of <i>Mtb</i> in both the acute and chronic phases of infection <i>in vivo</i>, and loss of viability <i>in vitro</i> when cultured on single carbon sources. Consistent with prior reports of <i>Mtb's</i> ability to co-catabolize multiple carbon sources, this <i>in vitro</i> essentiality could be overcome when cultured on mixtures of glycolytic and gluconeogenic carbon sources, enabling generation of an <i>fba</i> knockout (Δ<i>fba</i>). <i>In vitro</i> studies of Δ<i>fba</i> however revealed that lack of FBA could only be compensated for by a specific balance of glucose and butyrate in which growth and metabolism of butyrate were determined by <i>Mtb's</i> ability to co-catabolize glucose. These data thus not only evaluate FBA as a potential drug target in both replicating and persistent <i>Mtb</i>, but also expand our understanding of the multiplicity of <i>in vitro</i> conditions that define the essentiality of <i>Mtb's</i> FBA <i>in vivo</i>.</p></div

<i>Mtb</i> lacking FBA requires a balanced carbon diet for growth.

<p>Growth of WT and Δ<i>fba</i> was in media containing (<b>A</b>) 0.2% glucose with varying concentrations of butyrate and (<b>B</b>) 0.1% butyrate with varying concentrations of glucose. Bacteria were cultured in 96-well plates and absorbance was measured at the indicated time points. Data are means of triplicate cultures +/− SEM and representative of two independent experiments.</p

FBA essentiality is carbon source dependent.

<p>(<b>A</b>) Growth of replacement transformants of <i>Mtb</i> P_smyc-<i>fba</i>-<i>fba</i>::hyg with a plasmid not containing <i>fba</i> and thus resulting in Δ<i>fba</i> on agar plates containing the indicated carbon sources. (<b>B</b>) Growth of Δ<i>fba</i> in 7H9 base liquid media with identical carbon sources as in the above plate conditions.</p

FBA is required for replication and persistence of <i>Mtb</i> in mice.

<p>(<b>A</b>) Growth and survival of WT (squares) and FBA-DUC (circles) in mouse lungs (left panel) and spleens (right panel). Mice infected with FBA-DUC received doxy-containing food from the day of infection (day 0), day 10, day 35 or not at all as indicated. CFU were not detected in spleens from mice infected with FBA-DUC and treated with doxy starting day 0. The limit of detection was 4 CFU in lungs and spleens. Data are means ± SD of four mice, except for three data points which derive from 3 or 2 mice due to the appearance of atc/doxy resistant revertants in the lungs (day 57 FBA-DUC+doxy day 10, day 85 FBA-DUC+doxy day 10 and day 112 FBA-DUC+doxy day 35). (<b>B</b>) Gross pathology and H&E staining of lung sections from mice infected with FBA-DUC. Lungs were isolated at day 35 (upper panel) and day 112 (middle and lower panel) from mice not treated and administered doxy starting day 35 post infection. A second short course infection experiment reproduced the phenotype of FBA-DUC in mice not treated or treated with doxy starting on the day of infection.</p

FBA is required for replication in macrophages and growth and survival in mouse lungs.

<p>(<b>A</b>) Bacterial loads in resting and IFNγ activated mouse bone marrow derived macrophages (BMDM) infected with carbon-starved WT, <i>Δfba</i> and <i>Δfba</i>-comp. Data are means +/− SD of triplicate wells. *<i>P</i>≤0.05; **<i>P</i>≤0.005 by Student's t-test (<b>B</b>) Growth and survival of WT and <i>Δfba</i> in mouse lungs. Data are means +/− SD from four mice. Limit of detection was 4 CFU and <i>Δfba</i> was not detectable on days 10 and 21.</p