Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs.

Abstract

Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure-activity relationships of 1 and further increase potency and selectivity, 15 novel analogs (7-15 and 21-26) were synthesized and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3',3',5'-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED50 values of 1.0, 1.2, 0.9, and 1.3 mug/mL, respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over 5-fold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition.

• Authors: Kyoko Nakagawa-Goto, Tzu-Hsuan Chen, Chieh-Yu Peng, Kenneth F Bastow, Jiu-Hong Wu, Kuo-Hsiung Lee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 14 Pg. 3354-8 (Jul 12 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17569518 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkenes
• Antineoplastic Agents
• Ketones
• desmosdumotin C

Topics

• Alkenes (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Female
• Ketones (chemical synthesis, chemistry, pharmacology)
• Magnetic Resonance Spectroscopy
• Mice
• Spectrometry, Mass, Electrospray Ionization
• Spectrophotometry, Ultraviolet
• Structure-Activity Relationship