title: Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock.
abstract: Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.
authors.affiliation: Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, India.
authors.forename: Karothu Durga
authors.initials: KD
authors.lastname: Prasad
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Jamma
authors.initials: J
authors.lastname: Trinath
authors.affiliation: Department of Physics, Indian Institute of Science, Bangalore, India.
authors.forename: Ansuman
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India.
authors.forename: Kanagaraj
authors.initials: K
authors.lastname: Sekar
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Kithiganahalli N
authors.initials: KN
authors.lastname: Balaji
authors.affiliation: Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, India.
authors.forename: Tayur N
authors.initials: TN
authors.lastname: Guru Row
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D004731:Endotoxins / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D047069:Pyrazolones / Q000494:pharmacology*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D000880:Anthraquinones; D004731:Endotoxins; D047069:Pyrazolones; D054852:Small Molecule Libraries; C050637:losoxantrone; D048031:JNK Mitogen-Activated Protein Kinases