Synthesis of novel migrastatin and dorrigocin A analogues from D-glucal.
The synthesis of a range of analogues of the migrastatin macrolide core has been achieved from tri-O-acetyl-D-glucal in order to facilitate structure-activity studies. Efficient macrolactone formation was achieved in the presence of a reactive olefin, by increasing steric hindrance in the olefin environment. Acyclic analogues of migrastatin, structurally related to dorrigocin A, have also been prepared from D-glucal. The dorrigocin A analogues were prepared using the combination of the cross metathesis of ethyl 6-heptenoate with a glycal derivative and a subsequent allylic rearrangement-alkene isomerisation reaction (Perlin reaction). A synthetic route is thus provided that will enable dorrigocin A analogues to be prepared in parallel to migrastatin analogues in the search for novel anti-cancer and anti-arthritic therapeutics. Biological evaluation of one migrastatin and one dorrigocin A sugar derived analogue show that they inhibit proliferation and serum-induced migration of tumour and synovial cells at higher concentrations than evodiamine. Dorrigocin A analogues displayed similar potency to analogues of the migrastatin core.
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland.
Guillaume
G
Anquetin
Sarah L
SL
Rawe
Kevin
K
McMahon
Evelyn P
EP
Murphy
Paul V
PV
Murphy
D000475:Alkenes / Q000737:chemistry; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D002125:Calcium Gluconate / Q000737:chemistry*; D045744:Cell Line, Tumor / Q000187:drug effects; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D010881:Piperidones / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013583:Synovial Membrane / Q000187:drug effects*
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D007783:Lactones; D018942:Macrolides; D010881:Piperidones; C089606:dorrigocin A; C418199:migrastatin; D002125:Calcium Gluconate