Ted Tsutomu Fujimoto

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.

Quantitative structure-activity relationship studies of the fungitoxic properties of phenethyl 1,2,4-triazoles

Abstract A series of phenethyl triazoles was tested for activity in poisoned agar against Dreschlera sorokiniana, Piricularia oryzae , and a yeast sterol [ 14 C]demethylase assay. The effects of substitution on the carbon adjacent to the phenyl ring and halogenation of the phenyl ring on activity was examined by regressing activity against substituent physicochemical parameters in a Hansch-type analysis. Results indicate that one substituent on the carbon adjacent to the phenyl ring should be 6–7 A long. The terminal part of this substituent was negatively correlated to strong dipole moment, proton acceptor ability, or negative partial charge which implies a hydrophobic site. In general, the substitution patterns for the whole organism assays paralleled the activity of the demethylase assay. An exception was the para -phenyl position, whose optimum substituent varied by organism. The optimum substituent of the ortho -phenyl position varied with the substitution on the carbon adjacent to the phenyl ring. This interaction may be due to changes in the preferred conformation(s) of the molecule.

Synthesis and properties of a photoaffinity labeling reagent for protoporphyrinogen oxidases, the target enzymes of diphenyl ether herbicides.

A diazoketone 3 has been synthesized in two steps from acifluorfen 1, a diphenyl ether herbicide. Like the parent compound 1, the diazoketone 3 is toxic to plant cells and inhibits protoporphyrinogen oxidase, the molecular target of diphenyl ether herbicides. On photolysis of 3 in methanol, the generated carbene mainly undergoes the Wolff rearrangement to a ketene which further adds methanol, but many other products are observed. A tritiated derivative of 3 has been prepared which is suitable for photoaffinity labeling experiments.

Synthesis of (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone and (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone as colchicine mimetics

Abstract Colchicine mimetic (±)-4S,5R-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene ( 1 ) was epoxidized to afford a mixture of epoxides. The epoxides were separately converted in two steps, with high stereoselectivity, to two regioisomeric α-methoxyketones. One regioisomer, (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone ( 17 ), proved to be about 12-fold more potent than synthetic precursor 1 against HCT-116 tumor cells while the other regioisomer, (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone ( 16 ), and the synthetic intermediates tested showed no improvement in potency.