Synthesis of anti-tumour phosphatidylinositol analogues from glucose by the use of ring-closing olefin metathesis.
A divergent strategy is described for synthesis of the novel phosphatidylinositols 1-3. The synthetic approach commences from benzyl-protected methyl 6-iodo-6-deoxy-alpha-D-glucopyranoside, which undergoes zinc-mediated reductive fragmentation followed by vinyl Grignard addition and ring-closing metathesis to afford the key conduritol B intermediate 7. This can trifurcate to form three different benzyl-protected myo-inositol headgroups 4-6, which after phosphorylation and attachment of the glycerolipid part give phosphatidylinositols 1-3. Preliminary biological testing against human colon adenocarcinoma cells reveals that analogues 1-3 are significant anti-tumour agents.
Andresen
Thomas L
TL
Department of Chemistry, Technical University of Denmark, Lyngby.
Skytte
Dorthe M
DM
Madsen
Robert
R
D000230:Adenocarcinoma / Q000188:drug therapy; D000475:Alkenes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D003510:Cyclohexanes / Q000737:chemistry; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D010716:Phosphatidylinositols / Q000737:chemistry*
D000475:Alkenes; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D010716:Phosphatidylinositols; D005947:Glucose