title: Studies on chemical modification and biology of a natural product, gambogic acid (III): determination of the essential pharmacophore for biological activity.
abstract: Caged 4-oxa-tricyclo[4.3.1.0(3,7)]dec-2-one structural motifs are found in Garcinia natural products that demonstrate anti-tumor activity. Gambogic acid (GA, 1), the most abundant caged Garcinia xanthones, has been reported to be a promising anti-cancer agent. To identify the essential pharmacophore for its anti-tumor activity, a series of GA analogues that address potential key structural features for biological activity were synthesized, among which compound 11a displayed comparable in vitro anti-tumor activity as GA. Mechanistic studies on 11a determined that the compound induces apoptosis as well as arrests the G2/M phase of the cell cycle in HepG2 cells. The determination of the essential part of the scaffold found in GA to maintain anti-tumor effects, and the SAR based on the caged pharmacophore are reported and will provide key information for future anti-cancer drug development studies.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Dandan
authors.initials: D
authors.lastname: Gong
authors.forename: Changjun
authors.initials: C
authors.lastname: Lin
authors.forename: Shenglie
authors.initials: S
authors.lastname: Zhang
authors.forename: Meiyang
authors.initials: M
authors.lastname: Xi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Libing
authors.initials: L
authors.lastname: Wei
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D019253:Proto-Oncogene Proteins c-bcl-2; D044004:Xanthones; D051028:bcl-2-Associated X Protein; C052659:gambogic acid; D053148:Caspase 3