Development of practical syntheses of the marine anticancer agents discodermolide and dictyostatin.
Initially isolated in trace quantities from deep-sea sponges, the structurally related polyketides discodermolide and dictyostatin share the same microtubule-stabilizing antimitotic mechanism as Taxol. Discodermolide has been the focus of intense research activity in order to develop a practical supply route, and these efforts ultimately allowed its large-scale synthesis and the initiation of clinical trials as a novel anticancer drug. Similarly, the re-isolation and synthesis of dictyostatin continues to stimulate the biological and chemical communities in their quest for the development of new chemotherapeutic agents. This comprehensive review chronicles the synthetic endeavours undertaken over the last 15 years towards the development and realization of practical chemical syntheses of discodermolide and, more recently, dictyostatin, focusing on the methods and strategies employed for achieving overall stereocontrol and key fragment unions, as well as the design and synthesis of novel hybrid structures.
Florence
Gordon J
GJ
School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews KY16 9 ST, United Kingdom. gjf1@st-andrews.ac.uk
Gardner
Nicola M
NM
Paterson
Ian
I
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008386:Marine Biology; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D018942:Macrolides; D011753:Pyrones; C470814:dictyostatin; C071229:discodermolide