Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Sep 1;22(17):5707-13.
doi: 10.1016/j.bmcl.2012.06.077. Epub 2012 Jun 30.

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

Rachid Skouta  1 , Miki Hayano, Kenichi Shimada, Brent R Stockwell
Affiliations

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

Rachid Skouta et al. Bioorg Med Chem Lett. .

Abstract

A series of Pictet-Spengler condensation derivatives (tetrahydro-β-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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structures of small molecules explored in this study.
Figure 2
Figure 2
Compound 27 exhibits RAS synthetic lethality and induces non-apoptotic cell death.
Figure 3
Figure 3
Reactive oxygen species (ROS) levels in BJ-TERT/LT/ST/RASV12 cells.
Scheme 1
Scheme 1
Synthesis of barbituric acid analogs 8 and 10 linked through 1 carbon spacer, (a): OHCCH(OMe)2, 5% TFA, CH2Cl2, r.t., 17h. (b) KMnO4, THF, r.t., 17h. (c) AcOH/H2O (2:3 ratio), 120 °C, 1h. (d) (Boc)2O, DMAP, THF, r.t., 17h. (e) CH3I, NaH, DMF, r.t., 4h. (f) Diludine, proline (10 mol%), CH3CN, r.t., 48h. (g): HCl 4.0 M, dioxane, 80 °C, 17h.
Scheme 2
Scheme 2
Synthesis of barbituric acid analogs 15 and 17 linked through 2 carbon spacer, (a): C6H5CHO, toluene, then NaBH4, MeOH, r.t., 17h. (b) HCCCO2Me, MeOH then 5% TFA, CH2Cl2, r.t., 17h. (c) H2, Pd/C, AcOH, 120 °C, 1h. (d) (Boc)2O, DMAP, THF, r.t., 17h. (e) Dibal-H, THF, −78 °C -r.t., 17h. (f) DMP, NaHCO3, CH2Cl2, 2h, r.t., 17h.(g) Diludine, proline (10 mol%), CH3CN, r.t., 48h. (h): HCl 4.0 M, dioxane, 80 °C, 17h.
Scheme 3
Scheme 3
Synthesis of tetrahydro-β–carboline analogs 25–31, (a): CH2Cl2, 45 °C, 4h, then 5% TFA at −78 °C to r.t., 17h. (b) DIPEA, methyl chloroformate, CH2Cl2, r.t, 17h. (c) CH3I, NaH, DMF, r.t., 17h. (d) (Boc)2O (1 equiv.), DMAP, THF, r.t., 17h. (e) DIPEA, benzyl chloroformate, CH2Cl2, r.t, 17h. (f) BnBr, NaH, DMF, r.t., 17h.
Scheme 4
Scheme 4
Synthesis of tetrahydro-β–carboline analogs 33–35, (a): Glyoxal dimethyl acetal, 60% aqueous solution, CH2Cl2, 45 °C, 4h, then 5% TFA at −78 °C to r.t., 17h. (b) methyl chloroformate, DIPEA, CH2Cl2, r.t, 17h. (c) (Boc)2O (1 equiv.), DMAP, THF, r.t., 17h. (d) DIPEA, benzyl chloroformate, CH2Cl2, r.t, 17h. (e) BnBr, K2CO3, DMF, r.t., 17h.
See this image and copyright information in PMC

References

    1. There are numerous reports. For examples, see: Song Y, Wang J, Teng SF, Kesuma D, Deng Y, Duan J, Wang JH, Qi RZ, Sim MM. Bioorg. Med. Chem. Lett. 2002;12:1129. Liangxian C, Samit H, Langdon M, Thomas D. WO 2008127715. PTC Therapeutics, Inc.; USA: Carboline derivatives useful in the treatment of cancer and other diseases, PCT Int. Appl. 2008 Brent S, Seok WY. WO 2008103470. USA: Trustees of Columbia University in the City of New York; Preparation of carboline carboxylate derivatives as antitumor agents and oncogenic-RAS-signal dependent lethal compounds. PCT Int. Appl. 2008

    1. Ishida J, Wang HK, Bastow KF, Hu CQ, Lee KH. Bioorg. Med. Chem. Lett. 1999;9:3319. - PubMed
    1. Sakai R, Higa T, Jefford CW, Bernardinelli G. J. Am. Chem. Soc. 1986;108:6404.
    1. Rinehart KL, Kobayashi J, Harbour GC, Hughes RG, Jr, Mizsak SA, Scahill TA. J. Am. Chem. Soc. 1984;106:1524.
    2. Kobayashi J, Harbour GC, Gilmore J, Rinehart KL., Jr J. Am. Chem. Soc. 1984;106:1526.
    1. Leteurtre F, Madalengoitia JS, Orr A, Guzi TJ, Lehnert EK, Macdonald TL, Pommier Y. Cancer Res. 1992;52:4478. - PubMed

Publication types

MeSH terms

LinkOut - more resources