Synthesis and biological evaluation of novel analogues of dictyostatin Ian Paterson, a, * Nicola M. Gardner, a Karine G. Poullennec a and Amy E. Wright b a University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK b Harbor Branch Oceanographic Institution, 5600 US 1 North, Ft. Pierce, FL 34946, USA Received 19 January 2007; revised 9 February 2007; accepted 10 February 2007 Available online 14 February 2007 Abstract—Novel analogues of the microtubule-stabilising agent dictyostatin were designed using existing SAR information from the structurally related discodermolide, synthesised by a late-stage diversification strategy and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including those known to exhibit Taxol-resistance (AsPC-1, DLD-1, PANC-1, NCI/ ADR). Ó 2007 Elsevier Ltd. All rights reserved. The marine sponge-derived macrolide dictyostatin (1, Fig. 1) displays powerful growth inhibitory activity against a wide range of human cancer cell lines. 1,2 Its initial isolation by Pettit in 1994 in the Republic of Maldives enabled only a partial assignment of stereo- chemistry, hindering further synthetic development for nearly a decade. 1a Upon re-isolation by Wright, 1b sufficient natural dictyostatin became available in 2004 for a conclusive reassignment of the stereochemis- try by detailed NMR analysis combined with molecular modelling. 3 Subsequent total synthesis efforts con- firmed these structural revisions, 4 facilitating the pro- duction of larger quantities of this otherwise scarce marine macrolide for more extensive biological evalua- tion. Dictyostatin has been identified as a potent microtubule-stabilising agent (MSA) which like Taxol (2) binds to the taxoid binding site on b-tubulin. 1b,2 Its cytotoxicity is more pronounced than that of Taxol and is further retained against (P-glycoprotein efflux- mediated) Taxol-resistant cell lines. Thus, dictyostatin represents a promising antimitotic natural product drug lead for cancer chemotherapy development. The development of natural product analogues is an appealing goal from a pharmaceutical perspective, which provides exciting opportunities for structural sim- plification whilst maintaining biological potency. 5 A few dictyostatin analogues have been reported, 6 which, despite displaying potent cytotoxicities against some human cancer cell lines, appear to be much less active against those lines exhibiting Taxol-resistance. Their design was influenced by the structurally related MSA discodermolide (3), 7 for which a more substantial num- ber of analogue studies have been reported. 8,9 The resulting SAR information, together with more recent NMR experiments and binding studies, has led to the proposal of a b-tubulin bound bioactive conformation for discodermolide and a common pharmacophore model with the epothilones. 10,11 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.02.031 Keywords: Macrolide; Anticancer; Tubulin; Total synthesis. * Corresponding author. Tel.: +44 1223336407; e-mail: ip100@cam. ac.uk O OH HO OH OH O 1, dictyostatin O OH HO OH O O NH 2 O OH 3, discodermolide 1 26 1 24 7 14 OH O O HO AcO O O NH Ph AcO BzO HO Bz 2, Taxol Figure 1. Structures of dictyostatin, Taxol and discodermolide. Bioorganic & Medicinal Chemistry Letters 17 (2007) 2443–2447