3.4.6. Saiyacenol

Saiyacenols A (**84**) and B (**85**) (Figure 20) are triterpene polyethers that were isolated in 2012 from the red alga *Laurencia viridis*. Both inhibit cell proliferation of various human tumor cell lines (MM144 (human multiple myeloma), HeLa (human cervical carcinoma), CADO-ES1 (human Ewing's sarcoma), and show the best inhibitory activity against Jurkat (human T-cell acute leukemia) [78]. In 2015, saiyacenol C (**86**), and two hydroxylated derivatives **87** and **88**, were isolated from the same alga [79]. Although saiyacenols showed no activity toward a range of bacteria and fungal strains, compounds **85** and **86** avoid *Navicula* cf. *salinicola* and *Cylindrotheca* sp. growth, while compounds **87** and **88** were also active against germination of *Gayralia oxysperma*.

**Figure 20.** Structure of saiyacenols A–C (**84**–**86**) and their hydroxylated derivatives **87** and **88**.

More recently, Piñero and Fernández evaluated a range of natural and semisynthetic terpenoid polyethers against protozoan parasites of the *Trypanosoma* and *Leishmania*

genera [80]. Both **84** and **85** have anti-protozoal activity against *Leishmania amazonensis* (IC50 = 12.96 and 10.32 μM, respectively). Interestingly, saiyacenol A **84** was also effective against the highly resistant *Trypanosoma cruzi* (IC50 = 13.75 ± 2.28 μM). The semisynthetic 28-iodosaiyacenol B showed a high value (IC50 = 5.40 ± 0.13 μM) against *Leishmania amazonensis* and no toxicity to murine macrophage J774.A1. This turns it into a possible scaffold for antikinetoplastid drugs, as the data are comparable to those of the reference drug miltefosine (IC50 = 6.48).

Very recently, Nishikawa and Morimoto reported the asymmetric total synthesis of saiyacenol A, along with that of the related Aplysiol B [81]. In their research, an epoxideopening cascade was used to form both THF rings in the same step (Scheme 12). Thus, from advanced precursor **89**, treatment with CSA provoked two sequential 5-*exo* openings to form the oxygenated rings in *bis*-tetrahydrofuran **90**. The last step consisted of crossmethathesis with the ruthenium catalyst **91** and later bromoetherification with BDSB. Preliminary cytotoxicity was tested against P388, HT-29, and HeLa tumor cell lines, showing values of 5.4, 85, and >100 μM, respectively.

**Scheme 12.** Synthesis of saiyacenol A by Nishikawa and Morimoto.
