Synthesis and anticancer activity of new migrastatin analogs

MEDI 459

Guillaume Anquetin, guillaume.anquetin@ucd.ie1, Sarah L. Rawe, sarah.rawe@dit.ie2, and Paul V Murphy, paul.v.murphy@ucd.ie1. (1) Center for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Dublin, Ireland, (2) School of Chemical and Pharmaceutical Sciences, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland
Recently, the idea of targeting cell migration as an alternative strategy for the development of anti-cancer and potentially anti-angiogenic therapies has generated considerable interest. Migrastatin (2) is a natural product that inhibits cell migration. Migrastatin and dorrigocin (3) are shunt metabolites of iso-migrastatin (1) (Scheme 1). Although the total synthesis of migrastatin and its macrolide core have been achieved [1-4] there is still much to be learned about the structure activity relationships [5]. The initial biological evaluation of those analogues of the macrolide core structure of migrastatin has recently indicated much promise, providing agents ~1000 fold more potent than migrastatin itself in cell migration assays (4-7). To extend the understanding of the structure-activity relationships of the migratatin analogs synthesised, we investigated the impact of chemical modifications on positions C-8, C-10 and C-12 particulary. The synthesis of a range of analogues have been achieved from the carbohydrate precursor, tri-O-acetyl-D-glucal. Ring closing metathesis of intermediates with increased conformational constraint due to the presence of sterically hindered silyl protecting groups on oxygen has proven to be a key step in the synthetic routes to these types of analogues. Thus far, four migrastatin (8-11) and three dorrigocin (12-14) analogues have been synthesized, and their biological evaluation (anti-angiogenesis, anticancer activities, cytotoxic effects, ...) is currently under investigation and preliminary results show that novel macrocyclic structures inhibit proliferation and migration of breast tumour cells.

[1] Danishefsky, S. J. et al, J. Am. Chem. Soc., 2003, 6042-6043. [2] Cossy, J. Et al, Eur. J. Org. Chem., 2006, 4800-4808. [3] Danishefsky, S. J. et al, Tetrahedron Letters., 2002, 9039-9042. [4] Iqbal, J. et al, Tetrahedron Letters, 2006, 6083-6086. [5] Danishefsky, S. J. et al, J. Am. Chem. Soc., 2004, 11326-11337.

 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007