title: Design, synthesis, and characterization of rhein analogs as novel inhibitors of scavenger receptor A.
abstract: Scavenger receptor A (SRA) has been known as an immunosuppressive factor and therefore therapeutic inhibition of SRA may be potentially exploited for cancer immunotherapy. Our previously work suggested that rhein may act as an inhibitor of SRA in reversing immunosuppression of SRA during T cells activation. Herein, three deconstruction analogs of rhein, compound 1, 2, and 3, were further studied as inhibitors of SRA. These three compounds, particularly compound 1, also known as a natural product danthron, enhanced T cells activation, indicated by increased transcriptional activation of interleukin 2 (Il2) gene, production of IL-2 protein, and proliferation of T cells. Additionally, the interaction between these compounds and SRA was studied by molecular modeling. Compound 1 showed a favorable binding mode with the cysteine rich domain of SRA protein compared to compound 2 and 3. Collectively, those results would provide insight for future design and development of next generation rhein derivatives as SRA inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, United States.
authors.forename: Piyusha P
authors.initials: PP
authors.lastname: Pagare
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, United States.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: xywang@vcu.edu.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: yzhang2@vcu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D051117:Scavenger Receptors, Class A; C020491:rhein
keywords: Cancer immunotherapy; Danthron; Rhein; Scavenger receptor A