Hurghadolide A and swinholide I, potent actin-microfilament disrupters from the red sea sponge Theonella swinhoei

As part of our continuing interest in identifying anticancer drug leads from Red Sea marine organisms, we have investigated the sponge Theonella swinhoei. We report here the isolation and structure elucidation of swinholide A (1) and two new macrolides, swinholide I (2) and hurghadolide A (3). Swinholide I is the first derivative of swinholide A with hydroxylation at the side chain. Hurghadolide A possesses an unprecedented asymmetric 42-membered dilactone moiety and presents a novel skeleton of macrolides. The structural determinations were based on extensive interpretation of high-field NMR spectra and HRFABMS data. Swinholide I and hurghadolide A showed in vitro cytotoxicity against human colon adenocarcinoma (HCT-116) with IC₅₀ values of 5.6 and 365 nM, respectively. Furthermore, swinholide I and hurghadolide A caused disruption of the actin cytoskeleton at concentrations of 70 and 7.3 nM, respectively. In addition, both compounds were active against Candida albicans.