title: Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca(2+) channel and endothelin A/B2 receptor.
abstract: We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K(+))- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca(2+) channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca(2+) channels and ET peptides/receptors-mediated cardiovascular diseases.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gangneung Asan Hospital, Ulsan University College of Medicine, Gangneung 210-711, Republic of Korea.
authors.forename: Chong-Bin
authors.initials: CB
authors.lastname: Park
authors.affiliation: Department of Basic Science, Yonsei University Wonju College of Medicine, Wonju 220-701, Republic of Korea.
authors.forename: Chan Mug
authors.initials: CM
authors.lastname: Ahn
authors.affiliation: Department of Basic Science, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Sangtae
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Microbiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea; Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Daeho
authors.initials: D
authors.lastname: Kwon
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gangneung Asan Hospital, Ulsan University College of Medicine, Gangneung 210-711, Republic of Korea.
authors.forename: Won-Chul
authors.initials: WC
authors.lastname: Cho
authors.affiliation: Department of Microbiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea; Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Woon-Seob
authors.initials: WS
authors.lastname: Shin
authors.affiliation: Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Ye Sol
authors.initials: YS
authors.lastname: Um
authors.affiliation: Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea; Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea. Electronic address: bgpark@cku.ac.kr.
authors.forename: Byong-Gon
authors.initials: BG
authors.lastname: Park
authors.affiliation: Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea; Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea. Electronic address: sjlee@cku.ac.kr.
authors.forename: Seokjoon
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003474:Curcumin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003474:Curcumin
keywords: Curcumin; Curcumin mimic; Endothelin A/B(2) receptor antagonist; Endotheline-1; High potassium ion; L-type Ca(2+) channel blocker; Vasodilatation