curately reflects the tested biomarker profiles present in the wider human GC population. Thus, this panel of PDGCX models represents a valuable tool in understanding this lethal disease and serves as a powerful resource in enabling preclinical efficacy testing in oncology drug discovery. ~~ The rapid and progressive prevalence of antibiotic resistance urges for intensified research in the development of compounds with potent antimicrobial activities. Along these lines, the 1 / 22 Development of Chloramphenicol Homodimers improvement of the structural and physicochemical properties of existing antibiotics constitutes an extremely effective approach in the reduction of both toxic side effects and reported resistance. Peptidyl transferase activity, i.e. the activity of ribosomes to catalyze the peptidebond formation, resides in the large ribosomal subunit, and in prokaryotes is one of the most thoroughly validated targets for antibiotics, including chloramphenicol . CAM is a broad–spectrum bacteriostatic agent, consisting of a p-nitrophenyl ring attached to a dichloroacetyl tail via a 2-amino-1,3-propanediol moiety. As detected by crystallographic analysis in bacteria, it binds within the catalytic crevice of the PTase center, blocking essential ribosomal functions, such as peptide-bond formation, termination of translation, and translational accuracy. Contrary to bacteria, the chloramphenicol binding site in the archaeal Haloarcula marismortui 50S subunit is located at the entrance to the peptide exit-tunnel, which is overlapping with the binding site of macrolide antibiotics. Earlier equilibrium dialysis studies, reviewed by Pongs, have reported two binding sites for CAM on Escherichia coli ribosomes; a high affinity site verified by earlier and recent kinetic studies, and a low affinity site. Cross-linking of CAM to ribosomes of the bacterium E. coli and the archaeal Halobacterium halobium identified interactions of the drug with nucleotides clustered around the entrance to the peptide exit-tunnel. However in this study, high concentrations of CAM were required in order to produce crosslinking with 23S rRNA. Consequently, the functional significance of the second binding site of CAM remains elusive, whereas it has been firmly demonstrated that binding of CAM adjacent to the A-site of the PTase Neuromedin N chemical information center inhibits the accommodation of the 3-aminoacyl end of tRNA within the catalytic PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19758226 crevice. Nevertheless, the CAM2 site, if it really exists, could be exploited for the binding of CAM dimers bearing a correctly adjusted linker. Specifically, an optimally designed CAM dimer could promote binding of the first pharmocophore to the high affinity site and of the second one to the low affinity site. This could be easily achieved, since the unbound, but tethered pharmacophore acquires a very high local concentration from seeking out its cognate target within a sphere having a radius that corresponds to the length of the linker. Resistance to CAM has been frequently reported, and attributed to numerous mechanisms, such as target mutations or alterations, drug modifications, decreased membrane permeability, and over-expression of efflux pumps. However, the major concerns that hamper its clinical use relate to the adverse effects of causing hematologic disorders, like reversible bone marrow depression, aplastic anemia, and leukemia. To PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19755711 define its essential functionalities and to improve its pharmacological properties, CAM has been modified in many ways

The nucleobase moiety represents an alternative option for ASO modification

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