Structure–activity relationships of quassinoids for eukaryotic protein synthesis

Fukamiya, Narihiko; Lee, Kuo-Hsiung; Muhammad, Ilias; Murakami, Chihiro; Okano, Masayohis; Harvey, Isabelle; Pelletier, Jerry

doi:10.1016/j.canlet.2004.04.023

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Volume 220, Issue 1 , Pages 37-48, 18 March 2005

Structure–activity relationships of quassinoids for eukaryotic protein synthesis

Narihiko Fukamiya
- Faculty of Integrated Arts and Sciences, Hiroshima University, Kagamiyama 1-7-1, Higashi, Hiroshima 739-8521, Japan
Kuo-Hsiung Lee
- Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
Ilias Muhammad
- National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA
Chihiro Murakami
- Faculty of Integrated Arts and Sciences, Hiroshima University, Kagamiyama 1-7-1, Higashi, Hiroshima 739-8521, Japan
Masayohis Okano
- Faculty of Integrated Arts and Sciences, Hiroshima University, Kagamiyama 1-7-1, Higashi, Hiroshima 739-8521, Japan
Isabelle Harvey
- Dept. of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, Que., Canada H3G 1Y6
Jerry Pelletier
- Dept. of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, Que., Canada H3G 1Y6
- McGill Cancer Center, McIntyre Medical Sciences Building, McGill University, Montreal, Que., Canada H3G 1Y6
- Corresponding author. Address: McIntyre Medical Sciences Building, McGill University, Montreal, Que., Canada H3G 1Y6. Tel.: +1-514-398-2323; fax: +1-514-398-7384

Received 26 April 2004; accepted 27 April 2004.

Abstract

The effect of 63 quassinoids on eukaryotic protein synthesis has been investigated. Seventeen of the tested compounds showed potent in vitro activity, with IC₅₀s below 2μM for inhibition in Krebs ascites translation extracts. Sixteen of these quassinoids were also potent inhibitors of in vivo protein synthesis when exposed to Hela cells for 1h. Our results led to the following structure–activity relationships for quassinoids regarding translation inhibition. Activity is influenced by (i) the nature of the C-15 side chain, (ii) the nature of A ring modifications, (iii) the presence or absence of a sugar moiety, and (iv) the presence of an epoxymethano bridge.