p. 37-42
The ubiquitin-proteasome system controls a wide range of cellular events including cell cycle progression, and defects associated with this system result in various diseases including cancer and neurodegenerative disorders. Thus, the ubiquitin-proteasome system is emerging as a significant target in anticancer therapies. In addition, nowadays, inhibitors targeting the ubiquitin system including E1, E2 and E3 enzymes, the delivery system, and deubiquitinating enzymes are also candidates for anticancer drugs. In the continuing search for ubiquitin-activating enzyme (E1) inhibitors, hyrtioreticulins A-E (1-5) were isolated from the marine sponge Hyrtios reticulatus, along with a known alkaloid, hyrtioerectine B (6). Structural elucidation on the basis of spectral data showed that 1, 2, and 5 are new tetrahydro-13-carboline alkaloids, while 3 and 4 are new azepinoindole-type alkaloids. Possibly, 1-6 would be biosynthesized by the Pictet-Spengler reaction with L-tryptophan and L-alanine. While trans/cis ratios differ greatly among the three pairs of isolates, 0.67 (1/2), 0.53 (3/4), and 0.041 (5/6), thermodynamically unstable cis isomers are dominant for these pairs. Hyrtioreticulins A and B (1 and 2) inhibited El enzyme with IC50 values of 0.75 and 11 μg/mL, respectively, measured by their inhibitory abilities against the formation of an E1-ubiquitin intermediate. So far, only five E1 inhibitors, panapophenanthrine, himeic acid A (7), largazole, and hyrtioreticulins A and B (1 and 2), have been isolated from natural sources and, among them, 1 is the most potent El inhibitor.