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1.
Bioorg Med Chem ; 30: 115893, 2021 01 15.
Article in English | MEDLINE | ID: mdl-33333447

ABSTRACT

A series of novel bis-imidazolium salts was synthesized, characterized, and evaluated in vitro against a panel of non-small cell lung cancer (NSCLC) cells. Two imidazolium cores were connected with alkyl chains of varying lengths to develop a structure activity relationship (SAR). Increasing the length of the connecting alkyl chain was shown to correlate to an increase in the anti-proliferative activity. The National Cancer Institute's NCI-60 human tumor cell line screen confirmed this trend. The compound containing a decyl linker chain, 10, was chosen for further in vivo toxicity studies with C578BL/6 mice. The compound was well tolerated by the mice and all of the animals survived and gained weight over the course of the study.


Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Salts/chemical synthesis , Salts/chemistry , Salts/pharmacology , Structure-Activity Relationship
2.
ACS Omega ; 3(11): 16021-16027, 2018 Nov 30.
Article in English | MEDLINE | ID: mdl-31458240

ABSTRACT

Removal of chloride from CoCl2 with TlPF6 in acetonitrile, followed by addition of excess nitrosobenzene, yielded the eight-coordinate cobalt(II) complex salt [Co{Ph(O)NN(O)Ph}4](PF6)2, shown by single-crystal X-ray analysis to have a distorted tetragonal geometry. The analogous treatment of the bipyridyl complex Co(bpy)Cl2 yielded the mixed-ligand cobalt(II) complex salt [Co(bpy){Ph(O)NN(O)Ph}2](PF6)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](FeCl4)2. The use of TlPF6 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 PF6 - counteranion. Coordination number appears to be more important than d electron count in determining the geometry and metal-ligand bond distances of diphenylazodioxide complexes.

3.
Bioorg Med Chem Lett ; 27(4): 764-775, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28126518

ABSTRACT

Alkyl- and N,N'-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI-H460, NCI-H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC50 values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1-4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1-4 was over 4.4mg/mL using 2-hydroxypropyl-ß-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.


Subject(s)
Antineoplastic Agents/chemistry , Imidazoles/chemistry , Naphthols/chemistry , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Benzimidazoles/toxicity , Carbocyanines/chemistry , Carbocyanines/metabolism , Carbocyanines/toxicity , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemical synthesis , Imidazoles/toxicity , Kaplan-Meier Estimate , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence , Mitochondria/drug effects , Mitochondria/metabolism , Molecular Conformation , Salts/chemistry , Structure-Activity Relationship , Transplantation, Heterologous
4.
Bioorg Med Chem ; 25(1): 421-439, 2017 01 01.
Article in English | MEDLINE | ID: mdl-27876249

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/toxicity , Cell Line, Tumor , Cisplatin/pharmacology , Drug Screening Assays, Antitumor , Humans , Male , Mice, Inbred C57BL , Solubility , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 27(2): 196-202, 2017 01 15.
Article in English | MEDLINE | ID: mdl-27939175

ABSTRACT

A series of C2-alkyl substituted N,N'-bis(arylmethyl)imidazolium salts were synthesized, characterized, and tested for their in vitro anti-cancer activity against multiple non-small cell lung cancer cell lines by our group and the National Cancer Institute's-60 human tumor cell line screen to establish a structure-activity relationship. Compounds are related to previously published N,N'-bis(arylmethyl)imidazolium salts but utilize the historical quinoline motif and anion effects to increase the aqueous solubility. Multiple derivatives displayed high anti-cancer activity with IC50 values in the nanomolar to low micromolar range against a panel of non-small cell lung cancer cell lines. Several of these derivatives have high aqueous solubilities with potent anti-proliferative properties and are ideal candidates for future in vivo xenograft studies and have high potential to progress into clinic use.


Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Solubility , Structure-Activity Relationship
6.
Molecules ; 21(7)2016 Jul 16.
Article in English | MEDLINE | ID: mdl-27438815

ABSTRACT

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.


Subject(s)
Drug Discovery , Ligands , Molecular Docking Simulation , Proteins/chemistry , Binding Sites , Drug Discovery/methods , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Dynamics Simulation , Protein Binding , Proteins/antagonists & inhibitors , Small Molecule Libraries , Structure-Activity Relationship
7.
Med Chem Res ; 24(7): 2838-2861, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26446298

ABSTRACT

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.

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