Current Bioactive Compounds 2007, 3, 1-36 1 Spongiane Diterpenoids† Miguel A. González* Department of Organic Chemistry/Institute of Molecular Science, Dr Moliner 50, E-46100 Burjassot, Valencia, Spain Abstract: In this review we cover the structures, occurrence, biological activities and synthesis of all the spongianes and rearranged spongianes since their discovery in 1974. We have given special attention to structure revisions and biological properties of these polycyclic terpenoids of exclusive marine origin. However, an important part of the review describes the synthetic efforts in the field. Thus, this part has been subdivided into syntheses from other natural products, syntheses by biomimetic approaches and other approaches including enantioselective total syntheses. INTRODUCTION the family from sponges of the genus Spongia [9]. Thus, in Marine terpenoids are typical constituents of the secondary accordance with the IUPAC recommendations the saturated metabolite composition of marine flora and fauna. These hydrocarbon I, named ‘spongian’, was choosen as the fundamental isoprenoid-derived compounds are common in almost all marine parent structure with the numbering pattern as depicted in Fig. 1. phyla and show a wide range of novel structures. Although most of them are also present in terrestrial organisms, the occurrence of a O few skeletons is restricted to certain marine species. In this review 12 16 11 13 we focus our attention to diterpenoids characterized by polycyclic 20 1 C D O O structures having either the spongiane (I, C20) (Fig. 1) carbon 9 framework or several degraded or rearranged spongiane-derived 2 14 A 10 H 8 15 H H skeletons. 5 17 3 B Spongiane diterpenoids are bioactive natural products isolated 7 4 H 6 H exclusively from sponges and marine shell-less mollusks (nudibranchs), which are believed to be able of sequestering the 19 18 spongian-derived metabolites from the sponges, soft corals, I, spongiane skeleton 1, isoagatholactone hydroids and other sessile marine invertebrates on which they feed. Most of these compounds play a key role as eco-physiological mediators and are of interest for potential applications as CO2H therapeutic agents. O Spongianes having the characteristic carbon skeleton I (Fig. 1) CO H have been reviewed up to 1990 and listed in the Dictionary of H 2 terpenoids [1]. During the last two decades, many new members of this family of natural products have been isolated and described in H H specific reviews on naturally occurring diterpenoids by Professor HO2C Hanson [2], and the excellent reviewing work on marine natural products by Professor Faulkner [3,4], now continued by the team of 2, isoagathic acid 3, grindelic acid Professor Blunt [5,6], all of which have mainly covered the isolation and structural aspects of spongianes. A recent review on Fig. (1). the chemistry of diterpenes isolated from marine opisthobranchs, has also included articles on isolation and structure determination of The first known member of the spongiane family, isoaga- spongianes up to 1999 [7]. The latter also covered some synthetic tholactone (1), was discovered by Minale et al. from the sponge studies of this class of substances. To the best of our knowledge, Spongia officinalis about thirty years ago, being the first natural there is only one more report dealing with the initial studies towards compound with the carbon framework of isoagathic acid (2). the synthesis of spongianes [8]. We now provide full coverage of Structure (1) was assigned based on spectroscopic data and recent advances in the field including a comprehensive description chemical correlation with natural grindelic acid (3) [10]. of the synthetic approaches and syntheses reported in the literature To date, there are nearly 200 known compounds belonging to on spongianes up to march 2006. this family of marine natural products, including those with a spongiane-derived skeleton. Most of them present a high degree of STRUCTURE, OCCURRENCE AND BIOLOGICAL oxidation in their carbon skeleton, particularly at positions C-17 ACTIVITY and C-19 as well as on all the rings A-D. Given the variety of The semisystematic naming of this family of diterpenoids was chemical structures found in the spongiane family, we could group introduced in 1979 following the isolation of the first members of them according to the degree of oxidation as well as the degree of carbocyclic rearrangement of the parent 6,6,6,5-tetracyclic ring system. Thus, we have integrated most of them into two main *Address correspondence to this author at the Department of Organic groups: compounds having the intact spongiane skeleton and Chemistry/Institute of Molecular Science, Dr Moliner 50, E-46100 compounds either with an incomplete skeleton or resulting from an Burjassot, Valencia, Spain; Fax: +34 96 3544328; E-mail: [email protected] hypothetical rearrangement process, which has been proposed several times from a biosynthetic point of view. †An invited review in the series of bioactive compounds. 1573-4072/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. 2 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González Sponges are exposed to a variety of dangers in their environ- R4= H; R1= OAc, R2= R3= R 4= H; R1= OH, R2= R3= H, R4= OH; ment and this has led to the development of chemical defense R1= H, R2= R4= OH, R3= H) were isolated from the sponge Spongia mechanisms against predation. Nudibranchs feed on a variety of officinalis [27], whose methanol extract is active against sponges and are able of storing selected metabolites, even transform Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus them, for their own self defense. Thus, sponges and nudibranchs are sphaericus. It also inhibits the cell growth of HeLa cells with values a rich source of biologically active metabolites, and the spon- of ID50 1-5 mg/mL [11]. gianes, in particular, have displayed a wide spectrum of interesting Dorisenones A, B and D (5, R1= OAc, R2= H, R3= OH, R4= biological properties including antifeedant, antifungal, anti- OAc; R 1= OAc, R2= R4= H, R3= OH; R1= R 4= OAc, R2= R 3= H) microbial, ichthyotoxicity, antiviral, antitumor, antihypertensive, and dorisenone C (6, D13 R= Me) (Fig. 3) were isolated from the fragmentation of Golgi complex, as well as anti-inflammatory mollusk Chromodoris obsoleta [17], and sponges from the Aegean activity (see Table 1). Sea [28]. These compounds have displayed cytotoxic activities, in particular, dorisenone A has shown strong cytotoxicity against Intact Spongiane Skeleton L1210 and KB cancer cells [17]. The first subgroup contains compounds derived formally from the antimicrobial isoagatholactone (1) [11], and therefore O characterized by the functionalization present in ring D, a g-lactone AcO H ring D, in this case (Fig. 2). R O O O R1 R2 H H R1 R O O OAc 2 H H H R 3 (6) R3 R4 D13 R= Me H H D12 R= CHO (4) (5) R= CHO R1= H, R2 = Me, R3 = OAc R1= OH, R2 = R3 = R4 = H R1= H, R2 = CH2OAc, R3 = OAc R1= OAc, R2 = R3 = R4 = H Fig. (3). R1= H, R2 = Me, R3 = OH R1= OH, R2 = R3 = H, R4 = OH R = H, R = CHO, R = H R = H, R = R = OH, R = H 1 2 3 1 2 4 3 From the african mollusk Chromodoris hamiltoni [29], new R = R = H, R = CH OAc R = OAc, R = H, R = OH, R = OAc 1 3 2 2 1 2 3 4 spongianes having a functionalised C-17 such as compounds 6 (D12 R1= OH, R2 = CH2OAc, R3 = OAc R1= OAc, R2 = R4 = H, R3 = OH R = H, R = Me, R = H R = R = OAc, R = R = H R= CHO) and 6 (R= CHO) have been isolated. Their biological 1 2 3 1 4 2 3 activity has not yet been investigated. Fig. (2). During the past few years, new spongiane lactones characterised by an acid group at C-19 and like 6 (D13 R= Me) with For example, aplyroseol-1 (4, R1= H, R2= Me, R3= OAc), was a double bond between C-13 and C-14 (Fig. 4). For example, isolated from the dendroceratid sponges Aplysilla rosea [12,13], compound 7 (R= H) was isolated from the sponge Spongia Dendrilla rosea [14] Aplysilla polyrhapis [15], and Chelonaplysilla matamata along with the hemiacetal lactone 7 (R= a -OMe) and the violacea [16] and also from the nudibranches Chromodoris isomeric lactones 8 [30]. Compound 7 and 8 (R=H) have also been obsoleta [17] and Chromodoris inopinata [18]. Anti-tumor activity found in the sponge Coscinoderma mathewsi along with the lactol 7 against the P388 mouse leukaemia cell line in vivo showed no (R=OH) [31]. Lactol 7 (R=OH) also called spongiabutenolide A significant activity. and its hydroxy C-19 derivative, spongiabutenolide B, together with isomeric lactols, spongiabutenolides C-D, having the carbonyl group of the lactone moiety at C-16 have been found in a The sponge Aplysilla rosea also contained the lactone 4 (R1= H, Philippines marine sponge of the genus Spongia [32]. R2= CH2OAc, R3= OAc). From the tentatively identified mollusk Ceratosoma brevicaudatum, it was isolated the simplest member of O R the series with a functionalised C-17 (4, R1= H, R2= CHO, R3= H) [19]. The mollusk resulted to be Ceratosoma epicuria [20] and the synthetic compound showed some cytotoxicity against HeLa and O O HEp-2 cancer cells [21]. Aplyroseol-14 (4, R1= R3= H, R2= CH2OAc) and aplyroseol-16 H R H O (4, R1= OH, R2= CH2OAc, R3= OAc) have been isolated more recently also from the sponge Aplysilla rosea [24], whereas the H H cytotoxic g-lactone spongian-16-one (4, R1= H, R2= Me, R3= H) has HO2C HO2C been found in several species such as Dictyodendrilla cavernosa (7) (8) [22], Chelonaplysilla violacea [16,23], Aplysilla var.