title: Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3.
abstract: Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Asan, Chungnam 31538, Korea.
authors.forename: Seong-Su
authors.initials: SS
authors.lastname: Nah
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Hee Pom
authors.initials: HP
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA.
authors.forename: Udumula
authors.initials: U
authors.lastname: Venkatareddy
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gann
authors.affiliation: Department of Chemistry, Utah Valley University, 800 W University Pkwy, Orem, UT 84058, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rodriguez
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burt
authors.affiliation: Department of Chemistry, Utah Valley University, 800 W University Pkwy, Orem, UT 84058, USA.
authors.forename: Young Wan
authors.initials: YW
authors.lastname: Ham
authors.affiliation: Department of Dental Hygiene, Gwangyang Health Sciences University, Gwnagyang, Jeonnam 57764, Korea.
authors.forename: Yu Yeon
authors.initials: YY
authors.lastname: Jung
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010636:Phenols / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000070918:Synoviocytes / Q000378:metabolism
chemical_list: D010636:Phenols; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human