The mode of action of Ro 13-5478 and Ro 14-9578, monocyclic and tricyclic quinolone analogs, respectively, was examined for Escherichia coli and Staphylococcus aureus. The compounds showed antibacterial activity and effects on cell morphology, replicative DNA biosynthesis, and gyrase-catalyzed DNA supercoiling that were comparable to those shown by nalidixic acid and by oxolinic acid compounds. The results suggest that their site of action is DNA gyrase and that a bicyclic quinolone nucleus is not essential for activity.
Non-steroidal antiinflammatory drugs (NSAIDs) are commonly used for the treatment of inflammation, pain, and fever. Mechanistically, these compounds are believed to act via inhibition of the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to the prostaglandins (PGs). Although commercially available NSAIDS are efficacious antiinflammatory agents, significant side effects limit their use. Recently two forms of COX were identified- a constitutively expressed COX-1 and a cytokine-inducible COX-2. Commercially available NSAIDs like indomethacin inhibit both COX-1 and COX-2 suggesting the hypothesis that toxicities associated with NSAID therapy are due to inhibition of the non-regulated or constitutive form of COX (COX-1) in normal tissues, whereas therapeutic benefit derives from inhibition of the inducible enzyme, COX-2, at the site of inflammation. Therefore, a selective inhibitor of COX-2 may be anti-inflammatory without GI toxicity-providing a significant improvement over currently available NSAIDs.
// Jessica Wagner 1, 2 , Christina Leah Kline 1, 2 , Richard S. Pottorf 3 , Bhaskara Rao Nallaganchu 3 , Gary L. Olson 3 , David T. Dicker 1, 2 , Joshua E. Allen 4 , Wafik S. El-Deiry 1, 2 1 Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State University, Hershey, PA, USA 2 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA 3 Provid Pharmaceuticals, Inc., Monmouth Junction, NJ, USA 4 Oncoceutics, Inc., Hummelstown, PA, USA Correspondence to: Wafik S. El-Deiry, e-mail: wafik.eldeiry@fccc.edu Keywords: ONC201, TIC10, cancer, TRAIL pathway, Foxo3a, Akt, ERK Received: December 05, 2014 Accepted: December 09, 2014 Published: January 05, 2015 ABSTRACT We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.
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The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described. The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric groups to adopt conformations consistent with proposed bioactive conformations of the peptide. Compounds were synthesized by a stereoselective synthesis starting from L-glutamic acid. In a behavioral model of cognition in which TRH is active, the mimetics are potent, active compounds, exhibiting oral activity. One analog (26, (1S,3R,5(2S),5S)-5-[[5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-methyl]-5- [(1H-imidazol-5-yl)methyl]cyclohexaneacetamide) was radiolabeled for binding studies and evaluated in other binding assays and pharmacological tests. Competition binding of 26 vs [3H]MeTRH to rat brain slices suggests a two-site model for ligand binding with IC50's of 1 microM and 3 mM. Direct binding of [3H]-26 shows a biphasic curve with IC50's of 80 and 49 microM, respectively. Further studies would be needed to establish a link between the novel binding site(s) and the behavioral activity of 26 and TRH analogs.
1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (±)-1a – d and (±)-2 were designed by molecular modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the unsymmetrically N,N′-disubstituted acyclic sulfamides (±)-4a – d (Scheme 1) and (±)-11 (Scheme 2). These N-alkyl-N′-arylsulfamide precursors were synthesized by nucleophilic substitution of either a sulfamoyl-chloride or a N-sulfamoyloxazolidinone. Extension of base-induced cyclization methods from aliphatic to aromatic sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives (±)-3a – c were also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide fragment. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (±)-21a was solved, and the directionality of the H-bond donor (N−H) and acceptor (SO2) groups of the cyclic scaffold determined (Figs. 1 and 2). The pKa value of the N−H group in (±)-21a was determined by 1H-NMR titration as 11.9 (Fig. 3). Compounds (±)-1a – d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-digit millimolar concentration range.
The X-ray crystal structure of a complex between the human class II major histocompatibility complex (MHC) protein HLA-DR1 and a bispyrrolinone−peptide hybrid ligand has been determined to 2.7 Å resolution. The bispyrrolinone segment of the ligand closely mimics the polyproline type II conformation of peptide ligands bound to class II MHC molecules, emphasizing the considerable versatility of this peptidomimetic scaffold. Most hydrogen bonds conserved in all peptide/class II complexes are formed, and the side chains of the bispyrrolinone segment project into the same spaces as those occupied by side chains of bound peptides. Molecular modeling used in the design of the hybrid ligand was remarkably accurate in predicting the observed molecular interactions.
