title: New C-19-modified geldanamycin derivatives: synthesis, antitumor activities, and physical properties study.
abstract: Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 μM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.|b Department of Pharmacy , Jining Medical University , Jining 272067 , China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Liu
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhong
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Wang
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Wei-Qing
authors.initials: WQ
authors.lastname: He
authors.affiliation: a Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
authors.forename: Zhao-Yong
authors.initials: ZY
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D012995:Solubility; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; C000613167:thiazinogeldanamycin; C001277:geldanamycin
keywords: C-19-modified geldanamycin derivatives; antitumor activity; stability; synthesis; water solubility