The Callipeltoside Story
In their search for novel molecules of therapeutic benefit during the 1990s, Minale and his team collected extracts from the shallow water lithistid marine sponge Callipelta sp. Subsequent testing of these specimens revealed promising activity in cytotoxi
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The Callipeltoside Story James R. Frost and Steven V. Ley
Contents 1 Isolation 1.1 Structural Features and Assignment 1.2 Biological Activity of the Callipeltosides 2 Structural Investigations and Total Syntheses 2.1 Paterson Aglycon Synthesis (2001) 2.2 Trost Synthesis of Deschlorocallipeltoside A (8) 2.3 Trost Synthesis of Callipeltoside A (2002) 2.4 Evans Synthesis of Callipeltoside A (2002) 2.5 Paterson Synthesis of Callipeltoside A (2003) 2.6 Panek Synthesis of Callipeltoside A (2004) 2.7 Hoye Synthesis of Callipeltoside A (2010) 2.8 MacMillan Synthesis of Callipeltoside C (2008) 2.9 Ley Syntheses of Callipeltosides A, B and C (2012) 3 Conclusion and Final Remarks References
Abstract In their search for novel molecules of therapeutic benefit during the 1990s, Minale and his team collected extracts from the shallow water lithistid marine sponge Callipelta sp. Subsequent testing of these specimens revealed promising activity in cytotoxic assays by inhibiting in vitro proliferation of KB and P388 cells. Whilst a closer inspection of the extract revealed callipeltins A–C as the major metabolites responsible for the observed activity, further analysis led to the discovery of three additional cytotoxic components: callipeltosides A, B and C (each differing in the attached sugar). At the time, these molecules represented a structurally unprecedented class of polyketides, rightly drawing the attention of the synthetic
J. R. Frost (*) UCB Pharma, Slough, UK e-mail: [email protected] S. V. Ley (*) Department of Chemistry, University of Cambridge, Cambridge, UK e-mail: [email protected]
J. R. Frost and S. V. Ley
community. Although the connectivity of these molecules could be deduced by Minale, questions surrounding the absolute stereochemistry of the sugar moieties (C1’–C8’, D or L) and configuration of the trans-configured chlorocyclopropane with respect to the C1–C19 unit remained. Furthermore, the stereochemistry of the glycosidic linkage could not be conclusively determined. This chapter details the substantial effort of the synthetic community to elucidate the structure of these fascinating molecules from start to finish, describing nigh on 20 years of collective work by world leaders in the field. Graphical Abstract
Keywords Aglycon · Callipeltoside · Carbohydrate · Chlorocyclopropane · Macrocycle
1 Isolation Extracts from marine sponges have provided a large number of complex molecules that exhibit a wide range of biological activities. In their search for novel compounds that display antitumour and antiviral properties, Minale and his team examined an extract from the shallow water lithistid marine sponge Callipelta sp., located off New Caledonia [1, 2]. This specimen was found to inhibit the in vitro proliferation of P388 and KB cells whilst also providing protection against HIV. Further study of the extract indicated that callipeltins A–C were the major metabolites responsible for the biological activity [1, 2]. However, additional analysis of the dichloromethane extract of this marine sponge (2.5 kg free
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