**5. Conclusions**

Terpenes and related compounds represent an important family of marine-derived metabolites. The grea<sup>t</sup> number of studies focused on their biological activities and total synthesis remark their importance. We have summarized the most active compounds for a variety of bioactivities (see Table 2). *Trans*-oxylipid has shown nematocidal properties against *Haemonchus contortus* (LD50 = 1.8 ppm) and *Trichostrongyllus colubriformis* (LD50 = 9.9 ppm). These values, comparable to the commercial levamisole and closantel, make this compound an interesting scaffold for the development of antihelmintic substances. Though not related to drug development, we want to remark the biological interest of (+)-PMA. Its potent olfactory response in sea lampreys makes it very valuable for the control and conservation of lamprey populations. Efforts should be made in developing a total synthesis for this compound, as none has been reported to date. Mutafuran D has antifungal activity, showing a moderate value of MIC = 4 mg/mL against *Cryptococcus neoformans var. grubii*. Although not an impressive value, further studies could shed light on the structure–activity relationship of this brominated ene-yne tetrahydrofuran derivative. Furoplocamioid C could serve as a lead for novel biopesticides, as it has shown a potent antifeedant effect against *Leptinotarsa decemlineata*, with an EC50 of 19.1 nmol/cm2, *Myzus Persicae* (EC50 of 3.7 nmol/cm2), and *Ropalosiphum Padi* (EC50 of 1.6 nmol/cm2) but it has low mammalian toxicity and phytotoxic effects. With respect to antibacterial activity, heranopyrrole D has shown very good values against *Staphylococcus aureus* ATCC 25923 (IC50 = 1.8 mM), *Staphylococcus epidermidis* ATCC 12228 (IC50 = 0.9 mM), and *Bacillus subtilis* ATCC 6633 (IC50 = 1.8 mM); thus, the nitropyrrole moiety should be further studied to determine whether it plays an important role in its antibacterial behavior. On the other hand, though (+)-darwinolide shows a more moderate value against *Staphylococcus aureus* (IC50 = 33.2 μM), its selectivity towards the biofilm phase and its low toxicity makes it a very good lead for the development of antibiofilm-specific antibiotics.

Regarding antitumoral applications, there are several compounds that have shown very promising activities. Uprolide D acetate has cytotoxic activity against different tumor cell lines: HeLa cells (IC50 = 2.5 mM), CCRF-CEM T-cell leukemia (IC50 = 7.0 mM), HCT-116 colon cancer (IC50 = 7.0 mM), and MCF-7 breast adenocarcinoma (IC50 = 0.6 mM). Thyrsenol B has an impressive potential against murine lymphoid neoplasm P-388 cells (IC50 = 0.016 mM). Saiyacenol B shows antiproliferative activity against tumor cell lines MM144 human multiple myeloma (IC50 = 11.0 mM), HeLa human cervical carcinoma

(IC50 = 24.5 mM), CADO-ES1 human Ewing's sarcoma (IC50 = 14.0 mM), and possesses a very good value for Jurkat (human T-cell acute leukemia): IC50 = 2.7 mM. Furthermore, it presents antifouling activity against *Navicula* cf. *salinicola* (IC50 = 17.2 mM) and *Cylindrotheca* sp. (IC50 = 17.0 mM). Finally, (+)-varitriol is a very interesting example, as it is quite a simple molecule with powerful properties. It presents submicromolar activities against different cancer cell lines, namely RXF-393 (Renal cancer cell) GI50 = 0.16 μM; SNB-75 (CNS cancer cell) GI50 = 0.24 μM; and DU-145 (breast cancer cell) GI50 = 0.11 μM. Although some efforts have already been made and different total syntheses reported, we believe that further studies should point to the synthesis of analogs and the study of structure–activity relationships in this simple scaffold.

Regarding antiprotozoal activity, saiyacenol B shows a good IC50 of 10.3 mM against *Leishmania amazonensis*. Interestingly it was surpassed by its synthetic counterpart, 28-iodosaiyacenol B, with a value of IC50 = 5.4 mM pointing to an interesting effect of this 28-iodosubstitution. Alisiaquinone C presents antimalarial activity in vitro against the chloroquineresistant strains MC29 CQR (IC50 = 0.08 mM) and B1 CQR (IC50 = 0.21 mM), and the chloroquine-sensitive strain F32 CQS (IC50 = 0.15 mM). Though it presents a high toxicity, similar structures that preserve antimalarial activity and have reduced toxicity values could be developed. A possible lead for anti-inflammatory development is myrothecol: it shows antioxidant activity with an EC50 = 1.2 mg/mL (*S* isomer) and EC50 = 1.4 mg/mL (*R* isomer), inhibits nitric oxide formation, and displays anti-inflammatory activity. It is also a small molecule and, thus, its synthesis will require lower effort.

In conclusion, the tetrahydrofuran moiety is a common motif found in a variety of such compounds, which has meant a particular emphasis of researchers on the development of new methodologies for the synthesis of such derivatives. In this context, total synthesis is a powerful tool to have access to these natural products. Firstly, it is an invaluable means for the determination of the structure and total configuration of natural compounds since, in some cases, the available NMR methods are insufficient in definitively determining the structures of biologically relevant substances. Secondly, since extracting and purifying compounds from natural sources are difficult and time-consuming processes, total synthesis has emerged as a suitable solution for the production of larger amounts of compounds, thus bringing possibilities for further biological studies, the discovery of novel drug candidates, and the expansion of the medicinal chemistry frontiers.


**Table 2.** Summary of most active compounds for a range of bioactivities within this review.

