Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.

Purpose: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action.

Experimental Design: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice.

Sulfonamides as a new scaffold for hypoxia inducible factor pathway inhibitors.

Solid tumors generally grow under hypoxic conditions, a pathophysiological change, which activates the expression of genes responsible for malignant, aggressive, and treatment-refractory properties. Hypoxia inducible factor (HIF) is the chief transcription factor regulating hypoxia-driven gene expression. Therefore, the HIF pathway has become a critical target for cancer therapeutics development.

Highly chemo- and regioselective reduction of aromatic nitro compounds using the system silane/oxo-rhenium complexes.

The reduction of aromatic nitro compounds to the corresponding amines with silanes catalyzed by high valent oxo-rhenium complexes is reported. The catalytic systems PhMe(2)SiH/ReIO(2)(PPh(3))(2) (5 mol %) and PhMe(2)SiH/ReOCl(3)(PPh(3))(2) (5 mol %) reduced efficiently a series of aromatic nitro compounds in the presence of a wide range of functional groups such as ester, halo, amide, sulfone, lactone, and benzyl. This methodology also allowed the regioselective reduction of dinitrobenzenes to the corresponding nitroanilines and the reduction of an aromatic nitro group in presence of an aliphatic nitro group.

Total synthesis and biological evaluation of halipeptins A and D and analogues.

The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d.

Total synthesis of halipeptins: isolation of halipeptin D and synthesis of oxazoline halipeptin analogues.

The isolation from the marine sponge Leiosella cf. arenifibrosa and structural elucidation of halipeptin D (5), a relative of the previously isolated halipeptins A-C (1-3), is described along with the total synthesis of a number of oxazoline analogues (7 a-d and epi-7 c-d). The developed synthetic strategy provides a flexible entry into the various isomers of the polyketide domain of the halipeptins and improvises for a late stage construction of the oxazoline ring after a macrolactamization process which secures the required macrocycle.

Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway.

Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library.