FEATURE ARTICLE 166 Total Synthesis of Terpenoids Isolated from Caulerpale Algae and Their Inhibition of Tubulin Assembly Synthesis of Terpenoids Isolated fromCaulerpale Algae Laurent Commeiras, a Julien Bourdron, a,b Soazig Douillard, b Pascale Barbier, b Nicolas Vanthuyne, c Vincent Peyrot,* b Jean-Luc Parrain* a a UMR-CNRS 6178 SymBio, équipe Synthèse par voie Organométallique, Université Paul Cézanne, Aix-Marseille III, France Fax +33(4)91288861; E-mail: jl.parrain@univ.u-3mrs.fr b FRE-CNRS 2737, Interaction entre Systèmes Protéiques dans la Cellule Tumorale, Faculté de Pharmacie, Aix-Marseille II, France Fax +33(4)91835505; E-mail: vincent.peyrot@pharmacie.univ-mrs.fr c UMR 6180 ‘Chirotechnologies: Catalyse et Biocatalyse’, Laboratoire de Stéréochimie Dynamique et Chiralité, Université Paul Cézanne, Aix-Marseille III, France Received 28 September 2005 SYNTHESIS 2006, No. 1, pp 0166–018106.01.2006 Advanced online publication: 16.12.2005 DOI: 10.1055/s-2005-921760; Art ID: Z18505SS © Georg Thieme Verlag Stuttgart · New York Abstract: Total synthesis of four analogue terpenoids isolated from Caulerpa taxifolia was achieved in good yield with a total control of each double bond. Biological tests to compare the activities of in vitro tubulin polymerisation between the natural caulerpenyne and the synthetic caulerpenyne and its derivatives were also performed. Key words: total synthesis, caulerpenyne, dihydrorhipocephalin, furocaulerpin, terpenoids, microtubule polymerisation Introduction Marine algae of the order Caulerpales are known for their chemical defence against predators by producing second- ary metabolites. The majority of these compounds are ses- quiterpenoids and diterpenoids, often acyclic. The terminal 1,4-diacetoxybutadiene moiety is a functional group common to most of these metabolites and uniquely found in this group of marine algae. To date, more than thirty toxins with this moiety have been isolated from the Udoteaceae and Caulerpaceae families such as cauler- penyne, flexiline, dihydrorhipocephalin and crispatenine (Figure 1). 1 The 1,4-diacetoxybutadiene moiety represents an acetyl- ated bis-enol form of the 1,4-dialdehyde constellation, to which a high degree of biological activity is generally at- tributed. Indeed, some metabolites containing this moiety have been implicated in chemical defence against grazing fishes and invertebrates in herbivore-rich tropical waters and this has, for example, been proposed to explain the proliferation from Italy to Spain of Caulerpa taxifolia, a tropical green seaweed accidentally introduced in the Mediterranean sea. From Caulerpa taxifolia were isolated nine mono- and sesquiterpenes such as caulerpenyne 2 (CYN, 1) which represents the main secondary metabolite of this algae. CYN is well known for its important biological activity: it displays antineoplastic and antibacterial properties. 3 It in- hibits the first division of sea urchin eggs without affect- ing fertilization 4 and induces a transient cytoplasmic acidification followed by an efflux of protons. 5 In addi- tion, CYN alters ATP-dependent Ca 2+ storage in intracel- lular organelles, protein phosphorylation, and DNA synthesis. 4 Moreover, Fischel et al. showed that CYN in- hibited growth in eight human cancer cell lines. 6 Their study showed that in the presence of CYN, cells exhibited an early and marked shift into S phase followed by a blockage in the G 2 /M phase. Recently, we have demon- strated that natural CYN induced an inhibition of neuro- blastoma SK-N-SH cell line with an inhibitory concentration of 8±1 mM after 24 hours of incubation. No blockage in G 2 /M phase but an increase in cell death was observed. By immunofluorescence of the tubulin cyto- skeleton, we observed a modification of the microtubule network in presence of natural CYN. Moreover, natural CYN inhibits the tubulin polymerisation in vitro with an Figure 1 Some of the toxins isolated from Udoteaceae and Cauler- paceae algae AcO AcO OAc Caulerpenyne (1) AcO AcO O Taxifolial A (2) AcO AcO OAc Dihydrorhipocephalin (3) AcO Furocaulerpin (4) O AcO OAc OAc AcO OAc Flexiline Crispatenine