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 RelationshipABSTRACT
Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI50 ranging from 200 to 250⯵M over a period of 1â¯h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Organophosphorus Compounds/pharmacology , Urinary Bladder Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Mice , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Structure-Activity Relationship , Urinary Bladder Neoplasms/pathologyABSTRACT
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.
ABSTRACT
Three isostructural coordination networks of Ce, Pr, and Nd nitrate with 4,4'-bi-pyridine N,N'-dioxide (bpydo) are reported, namely poly[[tris-(nitrato-κ(2) O,O')cerium(III)]-bis-(µ2-4,4'-bi-pyridine N,N'-dioxide-κ(2) N:N')], [Ce(NO3)3(C10H8N2O2)2], poly[[tris-(nitrato-κ(2) O,O')praeseodymium(III)]-bis-(µ2-4,4'-bi-pyridine N,N'-dioxide-κ(2) N:N')], [Pr(NO3)3(C10H8N2O2)2], and poly[[tris(nitrato-κ(2) O,O')neodymium(III)]-bis-(µ2-4,4'-bi-pyridine N,N'-dioxide-κ(2) N:N'], [Nd(NO3)3(C10H8N2O2)2]. All three compounds are isostructural to the previously reported La analogue. The asymmetric unit of [Ln(NO3)3(µ2-bpydo)2] contains one lanthanide cation, two bpydo ligands, and three nitrate anions. Both bpydo ligands act as end-to-end µ2-bridges and display nearly ideal cis and gauche conformations, respectively. The bpydo ligands link the ten-coordinate Ln (III) cations, forming inter-digitating 4(4) grid-like layers extending parallel to (-101), where inter-digitation of layers is promoted by C-Hâ¯O inter-actions between nitrate anions and bpydo ligands. The inter-digitated layers are linked to sets of neighboring layers via further C-Hâ¯O and π-π inter-actions.
