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Chemical Compound Review

AG-F-00121     2-(2-diethylaminoethoxy)- 10,13-dimethyl-1...

Synonyms: AC1L2BLI, CTK8G3682, LS-186692
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Disease relevance of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one


High impact information on 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

  • NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl [6].
  • U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures [7].
  • U18666A, which induces the NPC phenotype, was used to modulate the intracellular vesicle traffic [7].
  • In cultured cells, BACE and PLSCR1 were colocalized in the Golgi area and in endosomal compartments, whereas they were co-redistributed in late endosome-derived multivesicular bodies when treated with U18666A, suggesting that both proteins share a common trafficking pathway in cells [8].
  • C(2)-ceramide abrogated the effect of U18666A on SRE-mediated gene transcription, suggesting cholesterol-independent regulation of SREBP [9].

Chemical compound and disease context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one


Biological context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

  • LDL binding, internalization, and lysosomal hydrolysis of LDL-cholesteryl esters are not affected by the presence of U18666A [13].
  • By selecting for cell growth in the presence of U18666A, we have identified a CHO cell line, designated U18R, that is resistant to U18666A-inhibition of LDL-derived cholesterol trafficking [14].
  • However, the mechanisms involved in U18666A-mediated apoptosis remain unknown [15].
  • Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons [16].
  • The microarray approach was used in conjunction with proteomics techniques to identify specific proteins which may serve as signature biomarkers during U18666A treatment [15].

Anatomical context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one


Associations of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one with other chemical compounds

  • Addition of an intracellular cholesterol transport inhibitor, either progesterone or U18666A, together with CP-113,818 blocked the toxic effect of CP-113,818 [21].
  • Exposure of C-6 glial cells to nanomolar quantities of U18666A caused a marked inhibition of total sterol synthesis from [14C]acetate or [3H]mevalonate within minutes [22].
  • Treatment of rat intestinal epithelial cell cultures with the oxidosqualene cyclase inhibitor, 3 beta-[2-(diethylamino)-ethoxy]androst-5-en-17-one (U18666A), resulted in an accumulation of squalene 2,3:22,23-dioxide (SDO) [23].
  • It showed a characteristic pattern of inhibition on exposure to trans-2-[4-(1,2-diphenylbuten-1-yl)phenoxy]-N,N-dimethylethylamine (tamoxifen; IC(50)=11.2 microM) and 3beta-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A; IC(50)=4.2 microM), two well known potent inhibitors of SI [24].
  • In view of this finding and the fact that U18666A and other OSC inhibitors are highly lipophilic cationic tertiary amines, we tested the hypothesis that the cataractogenic effect of U18666A is related to direct perturbation of lens membrane structure and function [2].

Gene context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

  • Addition of progesterone or U18666A to CHO cells elevated ABCA2 expression [25].
  • Agents that specifically blocked sphingomyelinase-mediated delivery of cholesterol to acyl-CoA:cholesterol acyltransferase (U18666A) or promoted cholesterol efflux to the medium (cyclodextrin) did not inhibit OSBP dephosphorylation [26].
  • Accumulation of tyrosinase in the endolysosomal compartment is induced by U18666A [27].
  • Specific targeting of cathepsin K and the vacuolar H+-ATPase at the ruffled border is blocked by U18666A [20].
  • In this model organism, the drug U18666A was shown to stimulate intra-endosomal budding, while an inhibitor of PI 3-kinase activity was found to have no effect on this process [28].

Analytical, diagnostic and therapeutic context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one


  1. The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease. Neufeld, E.B., Stonik, J.A., Demosky, S.J., Knapper, C.L., Combs, C.A., Cooney, A., Comly, M., Dwyer, N., Blanchette-Mackie, J., Remaley, A.T., Santamarina-Fojo, S., Brewer, H.B. J. Biol. Chem. (2004) [Pubmed]
  2. Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor. Cenedella, R.J., Jacob, R., Borchman, D., Tang, D., Neely, A.R., Samadi, A., Mason, R.P., Sexton, P. J. Lipid Res. (2004) [Pubmed]
  3. DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis. Di Stasi, D., Vallacchi, V., Campi, V., Ranzani, T., Daniotti, M., Chiodini, E., Fiorentini, S., Greeve, I., Prinetti, A., Rivoltini, L., Pierotti, M.A., Rodolfo, M. Int. J. Cancer (2005) [Pubmed]
  4. Effect of a hypocholesterolemic agent on cholesteryl ester metabolism in glioblastoma cells. Jeng, I., Klemm, N., Samson, L. Biochem. Pharmacol. (1985) [Pubmed]
  5. Cellular mechanism of U18666A-mediated apoptosis in cultured murine cortical neurons: Bridging Niemann-Pick disease type C and Alzheimer's disease. Koh, C.H., Cheung, N.S. Cell. Signal. (2006) [Pubmed]
  6. Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease. Patel, S.C., Suresh, S., Kumar, U., Hu, C.Y., Cooney, A., Blanchette-Mackie, E.J., Neufeld, E.B., Patel, R.C., Brady, R.O., Patel, Y.C., Pentchev, P.G., Ong, W.Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. Harada, M., Kawaguchi, T., Kumemura, H., Terada, K., Ninomiya, H., Taniguchi, E., Hanada, S., Baba, S., Maeyama, M., Koga, H., Ueno, T., Furuta, K., Suganuma, T., Sugiyama, T., Sata, M. Am. J. Pathol. (2005) [Pubmed]
  8. Identification of phospholipid scramblase 1 as a novel interacting molecule with beta -secretase (beta -site amyloid precursor protein (APP) cleaving enzyme (BACE)). Kametaka, S., Shibata, M., Moroe, K., Kanamori, S., Ohsawa, Y., Waguri, S., Sims, P.J., Emoto, K., Umeda, M., Uchiyama, Y. J. Biol. Chem. (2003) [Pubmed]
  9. Unsaturated fatty acid-mediated decreases in sterol regulatory element-mediated gene transcription are linked to cellular sphingolipid metabolism. Worgall, T.S., Johnson, R.A., Seo, T., Gierens, H., Deckelbaum, R.J. J. Biol. Chem. (2002) [Pubmed]
  10. Constitutive and vitamin C-induced, NO-catalyzed release of heparan sulfate from recycling glypican-1 in late endosomes. Mani, K., Cheng, F., Fransson, L.A. Glycobiology (2006) [Pubmed]
  11. Source of cholesterol for the ocular lens, studied with U18666A: a cataract-producing inhibitor of lipid metabolism. Cenedella, R.J. Exp. Eye Res. (1983) [Pubmed]
  12. Chronic exposure to U18666A induces apoptosis in cultured murine cortical neurons. Cheung, N.S., Koh, C.H., Bay, B.H., Qi, R.Z., Choy, M.S., Li, Q.T., Wong, K.P., Whiteman, M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  13. The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one. Liscum, L., Faust, J.R. J. Biol. Chem. (1989) [Pubmed]
  14. Characterization of Chinese hamster ovary cells that are resistant to 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one inhibition of low density lipoprotein-derived cholesterol metabolism. Liscum, L., Collins, G.J. J. Biol. Chem. (1991) [Pubmed]
  15. Neuronal apoptosis mediated by inhibition of intracellular cholesterol transport: Microarray and proteomics analyses in cultured murine cortical neurons. Koh, C.H., Peng, Z.F., Ou, K., Melendez, A., Manikandan, J., Qi, R.Z., Cheung, N.S. J. Cell. Physiol. (2007) [Pubmed]
  16. Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons. Koh, C.H., Whiteman, M., Li, Q.X., Halliwell, B., Jenner, A.M., Wong, B.S., Laughton, K.M., Wenk, M., Masters, C.L., Beart, P.M., Bernard, O., Cheung, N.S. J. Neurochem. (2006) [Pubmed]
  17. ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. Feng, B., Tabas, I. J. Biol. Chem. (2002) [Pubmed]
  18. Cholesterol modulates the membrane binding and intracellular distribution of annexin 6. de Diego, I., Schwartz, F., Siegfried, H., Dauterstedt, P., Heeren, J., Beisiegel, U., Enrich, C., Grewal, T. J. Biol. Chem. (2002) [Pubmed]
  19. The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells. Kobayashi, T., Vischer, U.M., Rosnoblet, C., Lebrand, C., Lindsay, M., Parton, R.G., Kruithof, E.K., Gruenberg, J. Mol. Biol. Cell (2000) [Pubmed]
  20. Pharmacological sequestration of intracellular cholesterol in late endosomes disrupts ruffled border formation in osteoclasts. Zhao, H., Väänänen, H.K. J. Bone Miner. Res. (2006) [Pubmed]
  21. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. Warner, G.J., Stoudt, G., Bamberger, M., Johnson, W.J., Rothblat, G.H. J. Biol. Chem. (1995) [Pubmed]
  22. Interrelationships of ubiquinone and sterol syntheses in cultured cells of neural origin. Volpe, J.J., Obert, K.A. J. Neurochem. (1982) [Pubmed]
  23. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis by oxylanosterols. Panini, S.R., Sexton, R.C., Gupta, A.K., Parish, E.J., Chitrakorn, S., Rudney, H. J. Lipid Res. (1986) [Pubmed]
  24. Cholesterol biosynthesis from lanosterol: molecular cloning, chromosomal localization, functional expression and liver-specific gene regulation of rat sterol delta8-isomerase, a cholesterogenic enzyme with multiple functions. Bae, S., Seong, J., Paik, Y. Biochem. J. (2001) [Pubmed]
  25. Human ATP-binding cassette transporter-2 (ABCA2) positively regulates low-density lipoprotein receptor expression and negatively regulates cholesterol esterification in Chinese hamster ovary cells. Davis, W., Boyd, J.T., Ile, K.E., Tew, K.D. Biochim. Biophys. Acta (2004) [Pubmed]
  26. Differential effects of sphingomyelin hydrolysis and cholesterol transport on oxysterol-binding protein phosphorylation and Golgi localization. Ridgway, N.D., Lagace, T.A., Cook, H.W., Byers, D.M. J. Biol. Chem. (1998) [Pubmed]
  27. Accumulation of tyrosinase in the endolysosomal compartment is induced by U18666A. Hall, A.M., Krishnamoorthy, L., Orlow, S.J. Pigment Cell Res. (2003) [Pubmed]
  28. Formation of multivesicular endosomes in Dictyostelium. Marchetti, A., Mercanti, V., Cornillon, S., Alibaud, L., Charette, S.J., Cosson, P. J. Cell. Sci. (2004) [Pubmed]
  29. Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model. Wu, J., Ellsworth, K., Ellsworth, M., Schroeder, K.M., Smith, K., Fisher, R.S. Brain Res. (2004) [Pubmed]
  30. Calcium activated proteolysis and protein modification in the U18666A cataract. Chandrasekher, G., Cenedella, R.J. Exp. Eye Res. (1993) [Pubmed]
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