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.
Original language | English |
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Pages (from-to) | 5097-5107 |
Number of pages | 11 |
Journal | Journal of Medicinal Chemistry |
Volume | 54 |
Issue number | 14 |
DOIs | |
Publication status | Published - Jul 28 2011 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery