title: Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
abstract: Nineteen new phenanthrene-based tylophorine analogues with various functional groups on the piperidine moiety were designed, synthesized, and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogues 15 and 21 showed approximately 2-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogues 23 and 24 with S- and R-configured substituents, respectively, at the piperidine 3'-position exhibited comparable cytotoxicity to that of PBT-1. Furthermore, mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cells and the NF-kB signaling pathway suggested that the compounds may exert their inhibitory activity on tumor cells through inhibition of activation of both Akt and NF-kB signaling pathway.
authors: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. qshi1@email.unc.edu
authors: Xiaoming
authors: X
authors: Yang
authors: Qian
authors: Q
authors: Shi
authors: Yi-Nan
authors: YN
authors: Liu
authors: Guiyu
authors: G
authors: Zhao
authors: Kenneth F
authors: KF
authors: Bastow
authors: Jau-Chen
authors: JC
authors: Lin
authors: Shuenn-Chen
authors: SC
authors: Yang
authors: Pan-Chyr
authors: PC
authors: Yang
authors: Kuo-Hsiung
authors: KH
authors: Lee
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D016328:NF-kappa B / Q000502:physiology; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D007212:Indolizines; C550445:N-(2,3-methylenedioxy-6-methoxyphenanthr-9-ylmethyl)-4'-hydroxylpiperidine; D016328:NF-kappa B; D010616:Phenanthrenes; D010618:Phenanthrolines; D010880:Piperidines; C473343:antofine; D051057:Proto-Oncogene Proteins c-akt; C004218:tylophorine