Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria.

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development.

Linear-selective hydroarylation of unactivated terminal and internal olefins with trifluoromethyl-substituted arenes.

We report a series of hydroarylations of unactivated olefins with trifluoromethyl-substituted arenes that occur with high selectivity for the linear product without directing groups on the arene. We also show that hydroarylations occur with internal, acyclic olefins to yield linear alkylarene products. Experimental mechanistic data provide evidence for reversible formation of an alkylnickel-aryl intermediate and rate-determining reductive elimination to form the carbon-carbon bond.

Efficient NQO1 substrates are potent and selective anticancer agents.

A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in cancer, but not normal cells, and discovering a compound that specifically interacts with it. The enzyme NQO1 is a potential target for personalized medicine, as it is overexpressed in many solid tumors.

An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.

Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS).

Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell death.

Deoxynyboquinone (DNQ) is a potent antineoplastic agent with an unknown mechanism of action. Here we describe a facile synthetic route to this anthraquinone, and we use this material to determine the mechanism by which DNQ induces death in cancer cells. DNQ was synthesized in seven linear steps through a route employing three palladium-mediated coupling reactions.

Synthesis and optical properties of bifunctional thiophene molecules coordinated to ruthenium.

A series of unsymmetrical bi- and tetrathiophenes have been synthesized with bipyridine and phosphonic acid functional groups. To do this, phosphonic esters were bonded to thiophenes and the thiophenes coupled to bipyridine. After synthesis of the thienylbipyridines, bis(bipyridine) ruthenium was coordinated to them through the bipyridines.