# Trepenoids in Marine Heterobranch Molluscs
## 3 Sesquiterpenoids
### Bicyclic Sesquiterpenoids
A recent chemical analyses of the South China Sea nudibranch's _Phyllidiella pustulosa_  
Figure 4: Structures of selected sesquiterpenoids from Heterobranch molluscs: (**20**) hogsonal; (**21**) austrodal; (**22**) 7-deacetoxy-oleuppuane; (**23**) pelseneeriol-1; (**24**) xidaoisocyanate A; (**25**) axisonitrile-3; (**26**) reticulidin A; (**27**) laveliidene; (**28**) nakafuran 8; (**29**) euryfuran; (**30**) pulescensin B; (**31**) julieannafuran; (**32**) millecrone A; (**33**) brasilenol. and _Phyllidia coelestis_, as well as their possible sponge prey _Acanthella cavernosa_, led to the isolation of a nitrogenous cadinane-type sesquiterpenoid, xidaoisocyanate A (24) (Figure 4), among other sesquiterpenoids and diterpenoids [130]. Moreover, _P. pustulosa_ from Fiji presents an isothiamate, axisonitrile-3 (25) (Figure 4), and several minor related sesquiterpenes [131]. The isothiamate displays a moderated antiplasmodal activity, being weakly cytotoxic (IC\({}_{50}\)\(>\) 20 \(\upmu\)g/ml) but strong growth inhibitor of _Mycobacterium tuberculosis_ (MIC 2 \(\upmu\)g/ml) [132]. Furthermore, a sesquiterpene isonitrile was also isolated as an antifouling agent from the Japanese _P. pustulosa_[123], and some other studies on the antifouling potential of _Phyllidia ocelata_, _P. varicosa_, _Phyllidia pustulosa_, and _Phillidiopsis krempfi_, found three more sesquiterpene isonitrile, the 10-epi-axisonitrile-3, 10-isocyano-4-cadinene, and 2-isocyanotrachyopsane, as well as a peroxide, 1,7-epidioxy-5-cadinene, and some more sesquiterpene isonitriles [122; 133]. _P. pustulosa_ and _Phyllidia ocellata_ from Australia, also present some stereoisomers of 4-isocyano-9-amorphene and of 10-isocyano-4-amorphene, respectively, while _Phyllidia picta_ from Bali contained the axane sesquiterpenoids petaisonitrile-1 and petaisonitrile-2 [134]. _Phyllidia_ sp. from Sri Lanka also contains 3-isocyano-theonellin, closely related to a cyanide from the demosponge _Axinyssa_[135]. Some nitrogenous bisabolene sesquiterpenes from these species also possess a potent antifouling activity against barnacle larvae in _in vitro_ assays [136; 137]. _P. varicosa_ presents two 9-thiocyanatopuppukeanane sesquiterpenes, isolated as an epimeric mixture, found also in its demosponge prey _Axinyssa aculeata_[138]. One of these compounds is present in the mantle, suggesting an implication in chemical defense, while both are present in the digestive gland, supporting a dietary origin. Both compounds display mild toxicity against brine shrimp and some antimicrobial activity against _Candida albicans_ and _Bacillus subtilis_. On the other hand, _P. coelestis_ from Thailand also presents two cytotoxic pupukeanane sesquiterpenoids [139]. Several studies suggest all these compounds may play an important role in the chemical defense of phyllidids against fish predators, and that this is also related to visual defenses [3; 140]. Contrastingly, _Reticulidia fungia_ from Okinawa is different from the rest of the family members in presenting two sesquiterpenes of a rare class of sponge compounds, the cytotoxic carbonimidic dichlorides, reticulidins A (26) and B (Figure 4) [141]. Furthermore, the dorid _Hexabranchus samguineus_ from South China presents a couple of sesquiterpenes, as well as other compounds, suggested to originate from its sponge diet [142]. Regarding Chromodoridids, bicyclic sesquiterpenoids are also present in several species. For example, the Atlantic species _Cadina laevis_ and _C. pellucida_ present laevidiene (27) (Figure 4), albicanol, and derivatives, some of them from the demosponge _Spongia agaricia_, on which they feed upon [143; 15; 144; 145; 146]. Furthermore, the spawn of _C. luteomarginata_ from British Columbia also presents a drimane sesquiterpenoid [147], and the slug is able to biosynthesize some of its terpenoids [148].