2. Academic Validation
  3. Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents

Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents

  • J Med Chem. 2011 Jul 28;54(14):5097-107. doi: 10.1021/jm200330s.
Xiaoming Yang 1,  Qian Shi,  Shuenn-Chen Yang,  Chi-Yuan Chen,  Sung-Liang Yu,  Kenneth F Bastow,  Susan L Morris-Natschke,  Pei-Chi Wu,  Chin-Yu Lai,  Tian-Shung Wu,  Shiow-Lin Pan,  Che-Ming Teng,  Jau-Chen Lin,  Pan-Chyr Yang,  Kuo-Hsiung Lee
Affiliations

Affiliation

  • 1 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
PMID: 21668000 DOI: 10.1021/jm200330s
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.

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