Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock

Prasad, Karothu Durga and Trinath, Jamma and Biswas, Ansuman and Sekar, Kanagaraj and Balaji, Kithiganahalli N and Row, Tayur Guru N (2014) Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock. In: SCIENTIFIC REPORTS, 4 .

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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.

Item Type:	Journal Article
Publication:	SCIENTIFIC REPORTS
Additional Information:	Copyright for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology Division of Chemical Sciences > Solid State & Structural Chemistry Unit Division of Interdisciplinary Sciences > Supercomputer Education & Research Centre Division of Physical & Mathematical Sciences > Physics
Date Deposited:	18 Jan 2015 06:35
Last Modified:	18 Jan 2015 06:35
URI:	http://eprints.iisc.ac.in/id/eprint/50689

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