Design and synthesis of Pictet-Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Skouta, Rachid¹  Hayano, Miki²  Shimada, Kenichi¹  Stockwell, Brent R.^1,3,4 

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[2] Columbia Univ, Dept Pharmacol, New York, NY 10027 USA

[3] Columbia Univ, Dept Chem, New York, NY 10027 USA

[4] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA

关键词: Pictet-Spengler;    RAS;    Synthetic lethal;    Structure-activity relationship (SAR);    Non-apoptotic;    Tetrahydro-beta-carboline;   

DOI  :  10.1016/j.bmcl.2012.06.077

来源: Elsevier

【 摘 要 】

A series of Pictet-Spengler condensation derivatives (tetrahydro-beta-carbolines) was designed, synthesized and evaluated for lethality against a panel of seven cancer cell lines. Seven compounds (2a, 13, 20, 21, 27, 29 and 34) showed lethality in at least five cell lines. Among these, compound 27 showed a unique selectivity towards oncogenic-RAS expressing BJ-TERT/LT/ST/RAS(V12) tumor cells, compared to non-transformed BJ-TERT cells. Further investigation revealed that 27 induces cell death without activation of caspases. This represents a useful new probe of non-apoptotic cell death and oncogenic-RAS synthetic lethality. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free