Sulfoglycolipids as a new molecules for tumor treatment : second year PH.D. presentation

Introduction & Aim of work: The main aim of the research project is to obtain new active compounds for cancer therapy by structural modifications of natural novosylacylglycerols (SQAGs). Which are one of the abundant sulfur-containing glycerolipids in the biotic world and are characterised by their unique sulfonic acid head group, a 6-deoxy-6-sulfo-glucose. [1] Their recently reported biological activities render them attractive targets for structural modifications and for the study of structure activity relationship. [2-9] Results and discussion: SQAG analogues have been synthesized in which the sulfoquinovose moiety is β-linked to the 2 position of glycerol carrying acyl chains of different length. A synthetic strategy has been used to selectively insert the proper chemical functionalities (i.e. sulfonate and acyl chains of different length) at the desired positions of the previously prepared glucosylglycerol skeleton to obtain the target compounds. The synthetic procedure has been modified with respect to that of previous year work because of poor yields and low reproducibility of deacetylation step. In particular the acetyl groups have been removed after the glycosylation step (step a) and substituted (step c) by chloroacetyl groups which can be then relatively eliminated (step f) with respect to the ester functionalities inserted on the glycerol moiety. Using the new scheme which is reported here the three target compounds have been synthesized. Reagents and conditions: a) BF3Et2O, DCM, RT, (85%), b) NaOMe, MeOH, RT, (90%), c) Chloroacetic Anhydride, Pyridine, DCM, -4OC, (93%), d) H2 Pd/C (10%), MeOH, (80%), e) Stearoyl chloride or lauroyl chloride or caproyl chloride, Pyridine, -10OC, (70-80%), f) Hydrazine Acetate, AcoEt/MeO, RT, (50-60%), g) Zinc Bromide, Tosyl Chloride, pyridine, -20 OC, (68-73%), h) Potassium Thioacetate, DMF, RT,(60-70%). i) Potassium Acetate, Oxone, Acetic Acid, RT, (30-40%). MCA= Monochloro acetyl., R= C17H35, C11H23, C5H11. , TsCl = Toluenesulfonyl chloride. Conclusion and Prospective: We have prepared the desired SQAG analogues (B) and the way which we have proceeded is described above. We have started with glucose penta-acetate and we have obtained the required sulfoderivative in good overall yields by using a synthetic strategy more advantageous than the one described in the first year report. Biological evaluation of the obtained compounds for their anti-angiogenesis activities (using a cell migration assay) and anti-tumor promoting activity (by Epstein Barr Virus Early Antigen assay) is in progress. Activation of protein kinase B (PKB or AKT) pathway control key cellular processes and contributes to tumorigenesis [9] and angiogenesis [10]. It could be interesting also to check their in vitro inhibitory activity against PKB, as recent studies have suggested us that our target compounds could be structurally related to some inhibitors of the PKB pathway. [9] Also the intermediate compounds A, lacking the sulfonate group, will be tested to check the influence of this anionic group. References: [1]Benning C. et.al. (1998) Ann.Rev.Plant Physiol. Plant Mol. Biol. 49,53-75. [2] Luescher-Mattli et.al. (2003) Current Medicinal Chemistry - Anti-infective Agents. 2, 219-225. [3] Murakami C. et.al.(2003) Biochim. Biophys. Acta 1645, 72-80. [4] Sakimoto I. et.al. (2006) Cancer Res 66, 2287-2295 [5] Shirahashi H., et.al. (1993) Chem. Pharm. Bull. 41, 1664-1666. [6] Colombo D., Ronchetti F., et.al.(1998) Cancer Lett. 123, 83-86. [7] Colombo D., Ronchetti F.,et.al. (2000) Cancer Lett., 161, 201-205. [8] Castillo, S. S. et. al. (2004) Cancer Res. 64, 2782. [9] Sale E.M. et. al. (2008) Cell. Mol. Life Sci. 65, 113. [10] Zheng M. et. al. (2004) Acta Physiologica Sinica, 56, 1-15.