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Chemical Compound Review

AC1L8WWP     (1R,5S,6S,7R,10S,14S,16S)- 6,10-dihydroxy-5...

Synonyms: CTK8F0383, NCI60_030304
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Disease relevance of C12153

  • To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B [1].
  • In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent [2].
  • Derivation of dihedral angles from CH-CH dipolar-dipolar cross-correlated relaxation rates: a C-C torsion involving a quaternary carbon atom in epothilone A bound to tubulin [3].

High impact information on C12153

  • In the paclitaxel-sensitive human cell lines we examined, epothilone B had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel [4].
  • This was not true for the inactive analogue of paclitaxel, baccatin III, or for an analogue of epothilone A, analogue 5, none of which stabilizes microtubules [5].
  • The increased drug sensitivity did not extend to epothilone A, a drug that binds to the same site and has a mechanism of action similar to that of paclitaxel, or colcemid, a drug with an opposing mechanism of action and a distinct binding site [6].
  • Thus, sarcodictyins A and B had IC50 values in the 200-500 nM range; paclitaxel, <10 nM (except in the resistant lines); and eleutherobin and epothilone A, 10-40 nM [7].
  • The C7 hydroxy group of cytotoxic epothilone A was selectively oxidized using PDC [8].

Biological context of C12153


Anatomical context of C12153

  • This activity of PGA2 was similar to that of the microtubule-stabilizing agents, paclitaxel (Taxol) and epothilone A, unlike the microtubule-depolymerizing agent, colchicine, which brought about quick neurite degeneration within 3 h [11].

Associations of C12153 with other chemical compounds

  • Based on their attractive in vitro biological profile epothilones have turned into important lead structures in anticancer drug discovery and hundreds of analogs and derivatives of epothilone A and B have been prepared and biologically characterized over the past four years [12].
  • The synthesis of the C7-C21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using alpha-pinene-derived reagents has also been described [13].

Gene context of C12153

  • Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins [2].

Analytical, diagnostic and therapeutic context of C12153


  1. A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Giannakakou, P., Gussio, R., Nogales, E., Downing, K.H., Zaharevitz, D., Bollbuck, B., Poy, G., Sackett, D., Nicolaou, K.C., Fojo, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  2. Gene expression profiling of epothilone A-resistant cells. Atadja, P., Yan-Neale, Y., Towbin, H., Buxton, F., Cohen, D. Novartis Found. Symp. (2002) [Pubmed]
  3. Derivation of dihedral angles from CH-CH dipolar-dipolar cross-correlated relaxation rates: a C-C torsion involving a quaternary carbon atom in epothilone A bound to tubulin. Carlomagno, T., Sánchez, V.M., Blommers, M.J., Griesinger, C. Angew. Chem. Int. Ed. Engl. (2003) [Pubmed]
  4. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). Kowalski, R.J., Giannakakou, P., Hamel, E. J. Biol. Chem. (1997) [Pubmed]
  5. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Mani, S., Huang, H., Sundarababu, S., Liu, W., Kalpana, G., Smith, A.B., Horwitz, S.B. Clin. Cancer Res. (2005) [Pubmed]
  6. Mutations at leucine 215 of beta-tubulin affect paclitaxel sensitivity by two distinct mechanisms. Wang, Y., Yin, S., Blade, K., Cooper, G., Menick, D.R., Cabral, F. Biochemistry (2006) [Pubmed]
  7. The coral-derived natural products eleutherobin and sarcodictyins A and B: effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Hamel, E., Sackett, D.L., Vourloumis, D., Nicolaou, K.C. Biochemistry (1999) [Pubmed]
  8. Oxidative and reductive transformations of epothilone A. Sefkow, M., Kiffe, M., Schummer, D., Höfle, G. Bioorg. Med. Chem. Lett. (1998) [Pubmed]
  9. Accompanying protein alterations in malignant cells with a microtubule-polymerizing drug-resistance phenotype and a primary resistance mechanism. Poruchynsky, M.S., Giannakakou, P., Ward, Y., Bulinski, J.C., Telford, W.G., Robey, R.W., Fojo, T. Biochem. Pharmacol. (2001) [Pubmed]
  10. The high-resolution solution structure of epothilone A bound to tubulin: an understanding of the structure-activity relationships for a powerful class of antitumor agents. Carlomagno, T., Blommers, M.J., Meiler, J., Jahnke, W., Schupp, T., Petersen, F., Schinzer, D., Altmann, K.H., Griesinger, C. Angew. Chem. Int. Ed. Engl. (2003) [Pubmed]
  11. Prostaglandins from a zoanthid: paclitaxel-like neurite-degenerating and microtubule-stabilizating activities. Han, C., Qi, J., Shi, X., Sakagami, Y., Shibata, T., Uchida, K., Ojika, M. Biosci. Biotechnol. Biochem. (2006) [Pubmed]
  12. Epothilone B and its analogs - a new family of anticancer agents. Altmann, K.H. Mini reviews in medicinal chemistry. (2003) [Pubmed]
  13. Studies towards the synthesis of epothilone A via organoboranes. Ramachandran, P.V., Chandra, J.S., Prabhudas, B., Pratihar, D., Reddy, M.V. Org. Biomol. Chem. (2005) [Pubmed]
  14. The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography. Nettles, J.H., Li, H., Cornett, B., Krahn, J.M., Snyder, J.P., Downing, K.H. Science (2004) [Pubmed]
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