title: Novel Natural Product-like Caged Xanthones Bearing a Carbamate Moiety Exhibit Antitumor Potency and Anti-Angiogenesis Activity In vivo.
abstract: DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability. 8n, which contains a bipiperidine carbamate moiety, displayed better drug properties and potential in in vivo antitumor activity. In addition, an antitumor mechanistic study suggested that 8n (DDO-6337) inhibited the ATPase activity of Hsp90 (Heat shock protein 90), leading to the inhibition of HIF-1a and ultimately contributing to its anti-angiogenesis and antitumor properties.
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Xiaoli
authors: X
authors: Xu
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Yue
authors: Y
authors: Wu
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Mingyang
authors: M
authors: Hu
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Xiang
authors: X
authors: Li
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Qichao
authors: Q
authors: Bao
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Jinlei
authors: J
authors: Bian
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
authors: Qidong
authors: Q
authors: You
authors: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.|Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 210009, China.
authors: Xiaojin
authors: X
authors: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D029760:Garcinia / Q000737:chemistry; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044004:Xanthones; C052659:gambogic acid