title: Novel natural-product-like caged xanthones with improved druglike properties and in vivo antitumor potency.
abstract: DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jinlei
authors.initials: J
authors.lastname: Bian
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.affiliation: 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. Electronic address: zxj@cpu.edu.cn.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D029760:Garcinia / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; C000605134:DDO-6306; D044004:Xanthones; C052659:gambogic acid; C009689:xanthone
keywords: Antitumor; Caged xanthones; Druglike; Gambogic acid; Natural-product-like