title: Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents.
abstract: Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wu
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Jau-Chen
authors.initials: JC
authors.lastname: Lin
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016196:S Phase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D010618:Phenanthrolines; C473343:antofine; C007160:cryptopleurine