The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

The syntheses and characterization of C 4 and C 5 substituted N,N'bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the lipophilicity of groups at the C 4 and C 5 positions plays a crucial role in modulating the efficacy against select non-small cell lung cancer cell lines tested. Compounds 11-17 were determined to be the most active against the panel of cell lines studied. Compounds 11 and 12 were examined by the National Cancer Institute's Developmental Therapeutic Program where they were tested against the NCI-60 human cancer cell line panel in a one-dose and five-dose assay. Compound 11 had high activity against the nine lung cancer lines tested while 12 had cytotoxic effects against 59 of the 60 cell lines. Compound 11 was also studied in a murine model to determine its in vivo toxicity.

A series of N,N′-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N1(N3)) and highly lipophilic substituents at the carbon atoms (C2 and C5(C6)) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin. The National Cancer Institute’s Developmental Therapeutics Program tested 1, 3–5, 10, 11, 13–18, 20–25, and 28–30 in their 60 human tumor cell line screen. Results were supportive of data observed in our lab. Compounds with hydrophobic substituents have higher anti-cancer activity than compounds with hydrophilic substituents.

Removal of chloride from CoCl 2 with TlPF 6 in acetonitrile, followed by addition of excess nitrosobenzene, yielded the eight-coordinate cobalt(II) complex salt [Co{Ph(O)NN(O)Ph} 4 ](PF 6 ) 2 , shown by single-crystal X-ray analysis to have a distorted tetragonal geometry. The analogous treatment of the bipyridyl complex Co(bpy)Cl 2 yielded the mixed-ligand cobalt(II) complex salt [Co(bpy){Ph(O)NN(O)Ph} 2 ](PF 6 ) 2 , whose single-crystal X-ray structure displays a trigonal prismatic geometry, similar to that of the iron(II) cation in the previously known complex salt [Fe{Ph(O)NN(O)Ph} 3 ](FeCl 4 ) 2 . The use of TlPF 6 to generate solvated metal complex cations from chloride salts or chlorido complexes, followed by the addition of nitrosobenzene, is shown to be a useful synthetic strategy for the preparation of azodioxide complex cations with the noncoordinating, diamagnetic PF 6 – counteranion. Coordination number appears to be more important than d electron count in determining the geometry and metal–ligand bond distances of diphenylazodioxide complexes.

Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and 15 N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins-a heretofore untapped reservoir for antibiotic agents.