IJOC  Vol.4 No.4 , December 2014
Synthesis of Biotinylated Galiellalactone Analogues
Abstract: Two biotinylated derivatives of the fungal metabolite galiellalactone (1) were synthesized in order to facilitate the investigation of the molecular mechanism of action of the galiellalactonoids. Galiellalactone is a STAT3-signaling inhibitor that inhibits growth in vitro as well as in vivo of prostate cancer cells expressing activated STAT3. To provide a suitable point of attachment for biotin, the 8-hydroxymethyl derivative (3) and its 7-phenyl analogue 4 were synthesized by a modified tandem Pd-catalysed carbonylation and intramolecular vinyl allene Diels-Alder procedure previously developed. The two primary alcohols obtained, 3 and 4, were coupled to biotin as the 6-aminohexanoic acid amide, activated as the acid chloride, yielding the derivatives 5 and 6.
Cite this paper: Escobar, Z. , Johansson, M. , Bjartell, A. , Hellsten, R. and Sterner, O. (2014) Synthesis of Biotinylated Galiellalactone Analogues. International Journal of Organic Chemistry, 4, 225-235. doi: 10.4236/ijoc.2014.44026.

[1]   Peyser, N.D. and Grandis, J.R. (2013) Critical Analysis of the Potential for Targeting STAT3 in Human Malignancy. Journal of OncoTargets and Therapy, 6, 999-1010.

[2]   Calò, V., Migliavacca, M., Bazan, V., Macaluso, M., Buscemi, M., Gebbia, N. and Russo, A. (2003) STAT Proteins: From Normal Control of Cellular Events to Tumorigenesis. Journal of Cellular Physiology, 197, 157-168.

[3]   Shodeinde, A.L. and Barton, B.E. (2012) Potential Use of STAT3 Inhibitors in Targeted Prostate Cancer Therapy: Future Prospects. OncoTargets and Therapy, 5, 119-125.

[4]   Hellsten, R., Johansson, M., Dahlman, A., Sterner, O. and Bjartell, A. (2008) Galiellalactone is a Novel Therapeutic Candidate against Hormone-Refractory Prostate Cancer Expressing Activated Stat3. Prostate, 68, 269-280.

[5]   Hellsten, R., Johansson, M., Dahlman, A., Sterner, O. and Bjartell, A. (2011) Galiellalactone Inhibits Stem Cell-Like ALDH-Positive Prostate Cancer Cells. PLoS One, 6, e22118.

[6]   Don-Doncow, N., Escobar, Z., Johansson, M., Kjellstrom, S., Garcia, V., Munoz, E., Sterner, O., Bjartell, A. and Hellsten, R. (2014) Galiellalactone Is a Direct Inhibitor of STAT3 in Prostate Cancer Cells. Journal of Biological Chemistry, 289, 15969-15978.

[7]   Johansson, M. (2002) Biosynthetic and SyntheticStudies of the Fungal Metabolite Gliellalactone. Ph.D. Dissertation, Bioorganic Chemistry, Lund University, Lund.

[8]   Gidlof, R., Johansson, M. and Sterner, O. (2010) Tandem Pd-Catalyzed Carbonylation and Intramolecular Vinyl Allene Diels-Alder Reaction toward Galiellalactone Analogues. Organic Letters, 12, 5100-5103.

[9]   Johansson, M., and Sterner, O. (2001) Synthesis of (+)-Galiellalactone. Absolute Configuration of Galiellalactone. Organic Letters, 3, 2843-2845.

[10]   Johansson, M. and Sterner, O. (2002) Synthesis of (-)-Galiellalactone. The Journal of Antibiotics, 55, 663-665.

[11]   Von Nussbaum, F., Hanke, R., Fahrig, T. and Benet-Buchholz, J. (2004) The High-Intrinsic Diels-Alder Reactivity of (-)-Galiellalactone; Generating Four Quaternary Carbon Centers under Mild Conditions. European Journal of Organic Chemistry, 2004, 2783-2790.

[12]   Best, M.D. (2009) Click Chemistry and Bioorthogonal Reactions: Unprecedented Selectivity in the Labeling of Biological Molecules. Biochemistry, 48, 6571-6584.

[13]   La Cruz, T.E. and Rychnovsky, S.D. (2007) A Reductive Cyclization Approach to Attenol A. Journal of Organic Chemistry, 72, 2602-2611.

[14]   Honda, T., Janosik, T., Honda, Y., Han, J., Liby, K.T., Williams, C.R., Couch, R.D., Anderson, A.C., Sporn, M.B. and Gribble, G.W. (2004) Design, Synthesis, and Biological Evaluation of Biotin Conjugates of 2-Cyano-3,12-dioxooleana- 1,9(11)-dien-28-oic Acid for the Isolation of the Protein Targets. Journal of Medicinal Chemistry, 47, 4923-4932.

[15]   Stivala, C.E. and Zakarian, A. (2011) Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries. Journal of the American Chemical Society, 133, 11936-11939.

[16]   Frizzle, M.J., Caille, S., Marshall, T.L., McRae, K., Nadeau, K., Guo, G., Wu, S., Martinelli, M.J. and Moniz, G.A. (2007) Dynamic Biphasic Counterion Exchange in a Configurationally Stable Aziridinium Ion: Efficient Synthesis and Isolation of a Koga C2-Symmetric Tetraamine Base. Organic Process Research & Development, 11, 215-222.

[17]   Alliot, J., Gravel, E., Pillon, F., Buisson, D.A., Nicolas, M. and Doris, E. (2012) Enantioselective Synthesis of Levomilnacipran. Chemical Communications, 48, 8111-8113.