Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
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.
Yang
Xiaoming
X
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. qshi1@email.unc.edu
Shi
Qian
Q
Liu
Yi-Nan
YN
Zhao
Guiyu
G
Bastow
Kenneth F
KF
Lin
Jau-Chen
JC
Yang
Shuenn-Chen
SC
Yang
Pan-Chyr
PC
Lee
Kuo-Hsiung
KH
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
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