title: C15-methoxyphenylated 18-deoxy-herbimycin A analogues, their in vitro anticancer activity and heat shock protein 90 binding affinity.
abstract: Benzoquinone ansamycins are important leads for the discovery of novel inhibitors of heat shock protein 90 (Hsp90), a promising target of cancer chemotherapeutics. Intrinsic hepatotoxicity caused by the benzoquinone moiety appeared to be a serious limitation to the development of these compounds. To solve this problem by rational structure optimization, a short series of C18-deoxy analogues of herbimycin A were designed based on putative interactions between the compound and the protein. Chemical synthesis of the target molecules were attempted by following the established synthetic route to the natural product, but resulted in the isolation of four serendipitous C15 phenylated final products. In vitro antiproliferative activity and Hsp90 binding affinity of the compounds were determined, suggesting the C18-oxygen of herbimycin A is removable and bulky lipophilic groups can be accommodated at C15 without loss of activity.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Nina
authors.initials: N
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Chuancai
authors.initials: C
authors.lastname: Bian
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Longlong
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China. Electronic address: mingxyu@imm.ac.cn.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D017828:Rifabutin; C020754:herbimycin
keywords: Anticancer activity; C15-phenylated analogue; C18-deoxy analogue; Herbimycin A; Hsp90 inhibitors