Further Probing\nthe Properties of a Unique Sponge-derived\nAlkaloid Through the Isolation of a New (−)-(5<i>E</i>)‑(8<i>R</i>)‑(14<i>Z</i>)‑Mycothiazole\nAnalogue

Scale-up\nisolation of (+)-(5<i>Z</i>)-(8<i>S</i>)-(14<i>Z</i>)-mycothiazole (<b>1</b>) from Vanuatu\nspecimens of <i>C. mycofijiensis</i> to semisynthesize (+)-(5<i>Z</i>)-(8<i>S</i>)-8-<i>O</i>-acetyl-(14<i>Z</i>)-mycothiazole (<b>2</b>) revealed a new diastereomer,\n(−)-(5<i>E</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>4</b>). The structure of <b>4</b> was determined using HRMS, NMR, and comparing optical rotation\nto (−)-(5<i>Z</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>3</b>) and <b>2</b>. The\nmaximum tolerated dose of <b>2</b> in mice was 0.1 mg/kg. The\nIC<sub>50</sub> of <b>4</b> in PANC-1 and HepG2 cancer cell\nlines was 111.6 and 115.0 nM. Evaluation of <b>4</b> in <i>C. elegans</i> showed similar oxygen consumption compared to <b>1</b>–<b>2</b>, and all compounds significantly increased\nthe lifespan. The <i>Z</i> orientation at Δ<sup>5,6</sup> is crucial for picomolar cytotoxicity but not for mitochondrial\ninhibition.