TY - JOUR
T1 - Synthesis of benzoxazole derivatives as interleukin-6 antagonists
AU - Kim, Darong
AU - Won, Hee Yeon
AU - Hwang, Eun Sook
AU - Kim, Young Kook
AU - Choo, Hea Young Park
N1 - Funding Information:
This work was supported by Mid-career Researcher Program through National Research Foundation (NRF) grant funded by the Korean Government (for ESH, NRF-2013R1A2A2A01068302).
Publisher Copyright:
© 2017
PY - 2017
Y1 - 2017
N2 - A growing number of studies have demonstrated that interleukin (IL)-6 plays pathological roles in the development of chronic inflammatory disease and autoimmune disease by activating innate immune cells and by stimulating adaptive inflammatory T cells. So, suppression of IL-6 function may be beneficial for prevention and treatment of chronic inflammatory disease. This study reports that a series of synthetic derivatives of benzoxazole have suppressive effects on IL-6-mediated signaling. Among 16 synthetic derivatives of benzoxazole, the compounds 4, 6, 11, 15, 17, and 19 showed a strong suppressive activity against IL-6-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 by 80–90%. While the cell viability was strongly decreased by compounds 11, 17, 19, the compounds 4, 6, and 15 revealed less cytotoxicity. We then examined the effects of the compounds on inflammatory cytokine production by CD4+ T cells. CD4+ T cells were induced to differentiate into interferon (IFN)-γ-, IL-17-, or IL-4-producing effector T cells in the presence of either the compound 4 or the compound 7. While the inactive compound 7 had no significant effect on the cytokine production by effector T cells, the active compound 4 strongly suppressed the production of inflammatory cytokines IFN-γ and IL-17, and also inhibited allergic inflammatory cytokines IL-4, IL-5, and IL-13 produced by effector Th2 cells. These results suggest that a benzoxazole derivative, compound 4 effectively suppresses IL-6-STAT3 signaling and inflammatory cytokine production by T cells and provides a beneficial effect for treating chronic inflammatory and autoimmune disease.
AB - A growing number of studies have demonstrated that interleukin (IL)-6 plays pathological roles in the development of chronic inflammatory disease and autoimmune disease by activating innate immune cells and by stimulating adaptive inflammatory T cells. So, suppression of IL-6 function may be beneficial for prevention and treatment of chronic inflammatory disease. This study reports that a series of synthetic derivatives of benzoxazole have suppressive effects on IL-6-mediated signaling. Among 16 synthetic derivatives of benzoxazole, the compounds 4, 6, 11, 15, 17, and 19 showed a strong suppressive activity against IL-6-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 by 80–90%. While the cell viability was strongly decreased by compounds 11, 17, 19, the compounds 4, 6, and 15 revealed less cytotoxicity. We then examined the effects of the compounds on inflammatory cytokine production by CD4+ T cells. CD4+ T cells were induced to differentiate into interferon (IFN)-γ-, IL-17-, or IL-4-producing effector T cells in the presence of either the compound 4 or the compound 7. While the inactive compound 7 had no significant effect on the cytokine production by effector T cells, the active compound 4 strongly suppressed the production of inflammatory cytokines IFN-γ and IL-17, and also inhibited allergic inflammatory cytokines IL-4, IL-5, and IL-13 produced by effector Th2 cells. These results suggest that a benzoxazole derivative, compound 4 effectively suppresses IL-6-STAT3 signaling and inflammatory cytokine production by T cells and provides a beneficial effect for treating chronic inflammatory and autoimmune disease.
KW - Benzoxazole derivatives
KW - IFN-γ
KW - IL-17
KW - IL-4
KW - IL-6-STAT3
UR - http://www.scopus.com/inward/record.url?scp=85018739851&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2017.03.072
DO - 10.1016/j.bmc.2017.03.072
M3 - Article
C2 - 28442260
AN - SCOPUS:85018739851
VL - 25
SP - 3127
EP - 3134
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 12
ER -