Sulfoglycolipids as new molecules for tumor treatment : first year presentation

Introduction & Aim of work: The sulfoglycolipids sulfoquinovosylacylglycerols (SQAG) are abundant sulfur-containing glycerolipids that are associated with photosynthetic organisms especially with a large number of marine algae [1]. Recently reported biological activities of SQAGs, including inhibitory effects on HIV-reverse transcriptase[2], mammalian DNA polymerase[3], proliferation of some cancer cell lines[3], angiogenesis (especially when coupled with tumor radiotherapy) [4] and also apoptosis induction[3], make these compounds very attractive for their potential in cancer therapy. Also, extractive SQAG mixtures are known to inhibit in vitro TPA induced tumor promotion stage [5]. The aim of this Ph.D. research project is to obtain new active compounds for cancer therapy by structural modification of natural sulfoquinovosylacylglycerols (SQAGs). SQAGs main structural feature is the anionic head group constituent sulfoquinovose, a derivative of glucose in which the 6-hydroxyl is replaced by a sulfonate group, -linked to the sn-3 position of a diacylglycerol (see structure A). The present work aims at the synthesis of molecules of general formula (B), as shown below, in which the sulfoquinovose moiety is -linked to the 2 position of glycerol carrying acyl chains of different length. Similar compounds, carrying a hydroxyl group instead of the sulfonate group (namely some glycoglycerolipid analogues), are known to be active as anti-tumor-promoters in TPA promoted carcinogenesis in vitro and in vivo experiments [6,7]. Results and discussion: We have obtained one of the desired compounds and the way which we have proceed is described below. We have started with glucose pentaacetate and in seven steps we have obtained the required sulfoderivative in good selectivity. Two steps are crucial in the synthesis, step d and g. We are now working to improve these two steps. The deacetylation reaction (step d) is very sensitive due to the presence of two fatty acyl chains. Reaction seems to go well but if we increase the reaction time then it results in the breakdown of acyl chains. The oxidation of thioester (step g) gave the most important problems as the compound which we got after this reaction is highly polar and is difficult to be extracted using organic solvents. Conclusion and Prospectives: First of all we have obtained one of the desired compounds. As we mentioned before two steps had low yields. So now we are working to improve the overall yield, eventually changing the synthetic strategies and also planning to prepare new molecules containing fatty acyl chains of different length. SQAGs originally derived from sea urchins are known to show antiangiogenesis activity especially when coupled with tumor radiotherapy)[5] Therefore, we are in project to test our SQAGs analogue angiogenic activity by in vitro cell migration experiments using cellular lines. (Human umbilical vein endothelial cells- HUVECs). 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.